nanomaterials for ocular drug delivery

Review

608

Nanomaterials for Ocular Drug Delivery

Shengyan Liu, Lyndon Jones, Frank X. Gu*

Efficient drug delivery to the eye remains a challenging task for pharmaceutical scientists. Dueto the various anatomical barriers and the clearance mechanisms prevailing in the eye,conventional drug delivery systems, such as eye drop solutions, suffer from low bioavail-ability. More invasivemethods, such as intravitreal injectionsand implants, cause adverse effects in the eye. Recently, anincreasing number of scientists have turned to nanomaterial-based drug delivery systems to address the challenges facedby conventional methods. This paper highlights recent appli-cations of various nanomaterials, such as polymeric micelles,hydrogels, liposomes, niosomes, dendrimers, and cyclodex-trins as ocular drug delivery systems to enhance the bioavail-ability of ocular therapeutic agents.

1. Introduction

Ocular drug delivery remains among the most challenging

approaches to the administration of therapeutic agents to

the humanbody. The eye is a small and complex organ that

is separated from the rest of the body by multiple layers of

biological barriers. Moreover, the internal ocular structures

and tissue are protected from the external environment by

the tight junctions of the corneal epithelium and the

mucosal surface. Therefore, the primary challenge of ocular

drug delivery is to circumvent these protective barriers in

order to achieve therapeutically effective concentrations of

drugs in the intraocular tissues. Thus, theobjectiveof ocular

drug administration is to treat ophthalmic diseases in a

localizedmanner, as opposed to serving as an intermediate

route toachievesystemicdrugactivity. This isanadvantage

for ocular drug delivery in that once the drug is successfully

delivered to the intraocular tissues the drug is not likely to

S. Liu, Prof. F. X. GuDepartment of Chemical Engineering, Waterloo Institute forNanotechnology, University of Waterloo, 200 University AvenueWest, Waterloo, ON, N2L 3G1, CanadaE-mail: [email protected]. L. JonesCentre for Contact Lens Research, School of Optometry,University of Waterloo, 200 University Avenue West, Waterloo,ON, N2L 3G1, Canada

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be cleared to the systemic circulation, which may cause

undesirable adverse effects.

Thereareaplethoraof vision-threateningoculardiseases

that require therapeutic treatment, and most of these

diseases are associated with the intraocular structures,

particularly the retina,macula, retinal pigment epithelium

(RPE), or choroid.[1] Typically, anti-inflammatory drugs,

anti-bacterial agents, or even angiogenesis inhibitors are

used to treat various types of local infections or blinding

disorders such as chronic uveitis, glaucoma, and choroidal

neovascularization;nevertheless, theefficiencywithwhich

these substancesare successfullydeliveredhas largelybeen

limited by the presence of a variety of ocular barriers. To

date, most common ophthalmic drugs are administered

topically in the form of eye drops to the corneal surface.

However, topically administered drugs suffer from low

bioavailability due to clearance mechanisms such as tear

turnover, inwhich the drugs are rapidly drained away from

the ocular surface through the puncta to the nasolacrimal

duct. Alternative delivery methods such as intravitreal or

periocular injections have been developed to improve the

bioavailability of the therapeutic agents, but due to the

invasive nature of these methods, side effects such as

retinal detachment or intravitreal hemorrhage have been

observed. The challenges affiliatedwith these conventional

methods of ocular drug delivery have led scientists to

contribute significant effort into developing advanceddrug

library.com DOI: 10.1002/mabi.201100419

Shengyan Liu received his bachelor of appliedscience degree (2010) in Nanotechnology Engin-eering from University of Waterloo (Canada). Heis currently a Ph. D. candidate in Chemical Engin-eering in University of Waterloo (Canada). Hereceived Ontario Graduate Scholarship (OGS) forhis Ph. D. study (2011). His Ph. D. study focuses ondeveloping smart nanoparticle drug deliverycarriers with sustained drug release phenomena,targeting affinity toward diseased tissues, andprolonged retention of the drug in the tissue forefficient ocular drug delivery.

Lyndon Jones is a professor at the School ofOptometry and Director of the Centre for Con-tact Lens Research at the University of Waterloo(Canada). He graduated in Optometry from theUniversity of Wales (UK), in 1985 and gained hisPhD from the Biomaterials Research Unit atAston University (UK) in 1998. His research inter-ests primarily focus on the interaction of noveland existing contact lens materials with theocular environment. He is a founding memberof the 20/20 Natural Sciences and EngineeringResearch Council (NSERC) Network for the Devel-opment of Advanced Ophthalmic Materials.

Frank Gu received his Ph.D. at Queen’s University(Canada), where he majored in chemical engin-eering and was awarded with Canada GraduateScholarship from Canadian Natural Sciences andEngineering Research Council (NSERC). In 2006,he was awarded with NSERC PostdoctoralFellowship to join the Laboratory of ProfessorRobert Langer at the Massachusetts Instituteof Technology (USA). In 2008, Frank joinedthe Department of Chemical Engineering atthe University of Waterloo. His current research

Nanomaterials for Ocular Drug . . .

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delivery systems that provide targeted therapy with

increased bioavailability.[2,3]

An ideal ocular drug delivery system should possess key

properties, including: (i) a controlled and sustained release

profile to maintain therapeutic concentration of the drug

for a prolonged period of time to reduce the frequency of

administration; (ii) specific targeting and prolonged

retention in the diseased tissues to improve therapeutic

efficiency and mitigate side effects; and (iii) patient-

friendly delivery routes that minimize or eliminate side

effects resulting directly from these administration

methods. At present, nanocarrier-based ocular drug

delivery systems appear to be the most promising tool to

meet the primary requirements of an ideal ocular delivery

system. Nanocarriers, due to their small sizes, are likely to

havehighdiffusivity acrossmembranes suchas the corneal

epithelium: a significant number of studies have already

demonstrated that the use of such nanomaterials via

topical administration improved the corneal permeability

of drugs.[2–5] Similarly, due to their high surface-area-to-

volume ratio, nanocarriers may also show improved

interaction with the outer mucous membrane of the

corneal surface, prolonging the retention of the topically

administered drug. Ongoing advances in developing

improved nanocarrier-based ocular drug delivery systems

may not only serve to enhance the delivery of drugs to the

ocular surface, but also provide new possibilities of

effectively delivering therapeutic agents to intraocular

tissues such as the retina or choroid, using non-invasive

delivery methods. This review highlights some of the most

recent findings in the utilization of nanomaterials, such

as polymeric micelles, hydrogels, liposomes, niosomes,

dendrimers, and cyclodextrins (CDs), for enhanced ocular

drug delivery performance (Figure 1).
interests are in the development of biomaterialsfor nanomedicine and biopharmaceuticsapplications. 2. Challenges of Conventional Ophthalmic
Drug Delivery

Difficulties in delivering drugs through the ophthalmic

route arise from the anatomy and the physiology of the eye

(Figure 2), an organ which is divided into anterior and

posterior segments. Topical drug administrations, such as

eye drops, suspensions, or ointments, are the most

preferred route of delivery to the anterior segment of the

eye, due to the ease of administration and low cost.

However, local drug administration to the anterior portion

of the eye by topical application is significantly limited by

the clearance mechanisms of the corneal surface, which

include lacrimation, tear dilution, and tear turnover.[6]

In addition, topically administered drugs are generally

absorbed either through the corneal route (cornea !aqueous humor! intraocular tissues) or non-corneal route

(conjunctiva ! sclera ! choroid/RPE),[6] which further

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limits the amount of drug that is ultimately absorbed in the

intraocular tissues.Due to these clearancemechanismsand

ocular barriers, less than 5% of the total administered drug

reaches the aqueous humor.[7] For example, after admin-

istration of a common eye-drop solution containing 0.05%

cyclosporine to treat dry eye syndrome, more than 95% of

the drug reaches systemic circulation through transnasal

or conjunctival absorption.[8]

The administration of drugs to the posterior portion of

the eye is evenmore challenging, due to the lack of cellular

components in the vitreous body, which reduces the

convection of molecules to the posterior segment. Efficient

drug delivery to the posterior segment of the eye is a

challenge faced by many pharmaceutical researchers, as

most blinding diseases are associated with the posterior

segment.[9] Systemic administration has also been used to

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Figure 2. The anatomy of the eye illustrating various ocular barriers and various mechani(2) intravitreal injection, (3) periocular injections [(3a) sub-conjunctival, (3b) peribulbar, (3cadministration.

Figure 1. A schematic illustration of different nanomaterial-based ocular drug deliverysystems. Polymeric micelles are NPs self-assembled from amphiphilic copolymers with theability to encapsulate hydrophobic drugs in the core of the particles. Hydrogel colloids are3D networks of water-soluble polymers which have the ability to incorporate hydrophilicdrugs in the 3D network. Liposomes/niosomes are vesicle structures with both lipophilicand hydrophilic phases, and therefore can encapsulate both hydrophobic and hydrophilicdrug components. Dendrimers are 3Dhighly branched tree-structuredmacromolecules thatcan encapsulate hydrophobic drugmolecules since they possess internal empty cavities andopen conformations for low generation dendrimers. CDs are a family of cyclic oligosac-charides, composed of six to eight glucose units which have been shown to improvepharmacokinetic properties of many drugs through the formation of an inclusion complex.

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S. Liu, L. Jones, F. X. Gu

deliver therapeutic agents to the poster-

ior segment of the eye; however, this

route of administration requires large

administration doses because of the

inner and outer blood-retinal barriers

that separate the retina and the vitreous

humor from the systemic circulation:[10]

studies to date have shown that less than

2% of systemically administered drugs

reaches the vitreous cavity.[6] High

administration doses or frequent admin-

istration directly translates to poor

patient compliance and increased risk

of systemic side effects.

Recently, intravitreal injections and

vitreal implants have been investigated

in order to achieve therapeutic concen-

trations at the posterior segment,

although both of these administration

options are very invasive methods with

high degrees of risk.[2] Currently, intravi-

treal injections of drugs such as bevaci-

zumab or ranibizumab are being tested

to treat vascular diseases associated

with the posterior segment of the eye,

including retinopathy of prematurity[11]

or choroidal neovascularization,[12]

respectively. Frequent administration

sms of drug delivery: (1) topical administration,) sub-tenon, (3d) retrobulbar)], and (4) systemic

im www.MaterialsViews.com


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through the intravitreal route is associatedwith short-term

adverse effects such as retinal detachment, endophthalmi-

tis, intravitreal hemorrhage, and increased risk of cataract

development.[4,6] More recently, periocular drug delivery

has been investigated as a less invasive method, compared

to intravitreal administration, in order to achieve high drug

concentrations in the vitreous cavity.[13] Periocular admin-

istration refers to the injection of the drug in the vicinity of

theocularorgan, suchas thesub-conjunctival, sub-tenon, or

parabulbar regions, so that the drugs can reach the vitreous

cavity by crossing the sclera, choroid, and RPE barriers.[13]

However, periocular drug administration is also not with-

out side effects, including a rise in intraocular pressure

(IOP), cataract development, hyphema, strabismus, and

corneal decompensation.[6]Asa result, topical drugdelivery

carriers that possess enhanced permeability across corneal

membranes and prolonged retention of the carriers in the

ocular moiety are still largely preferred over intravitreal

or periocular injections.
Figure 3. Schematic illustration of the particle-laden lens insertedin the eye. Reproduced with permission from ref.[21].
3. Contact Lenses in Ocular Drug Delivery

One of the earliest advancements in ocular drug delivery

came from the idea of using contact lenses as a sustained

drug delivery system.[6,14–16] In 2007, there were about

35 million contact lens wearers in North America alone,

and the number is expected to have risen continuously to

date.[17] The idea of using contact lenses as drug delivery

tool, therefore, has been considered very practical. The

contact lens drug delivery system is typically prepared by

soaking commercial products in a drug solution, allowing

retentionofdrugs in thehydrogelmatrix. Subsequently, the

drug is allowed to be released at the corneal surface upon

application of the lens on the eye (Figure 3). The purpose

of using the contact lens drug delivery system is to

increase the residence time of drugs on the corneal surface,

compared to topical application, to increase the amount of

corneal absorption of these drugs. A mathematical model

was used to postulate that as much as 50% of the drug

released from contact lens could be absorbed by the cornea,

but in vivo studies have yet to confirm this hypothesis.[18]

The drug release from the lens is governed by a simple

diffusion mechanism, which typically results in a burst

releaseofdrugsfortheinitial fewhours.[19]Therefore, several

studies have focused on using additional components in the

contact lenses to control the release rate of the drugs.

Ciolino et al. used the formulation of a poly[(lactic acid)-

co-(glycolic acid)] (PLGA) film, which is an FDA approved

biocompatible polymer that has shown tobe able to control

drug-release kinetics, coated with poly(hydroxyethyl

methacrylate) (pHEMA) hydrogel layers to control the

release of ciprofloxacin.[19] The formulation resulted in

steady zero-order release of ciprofloxacin for up to 4weeks.




When the PLGA filmwas not present, ciprofloxacin released

at a rate more than three times faster from the pHEMA

hydrogel than from the PLGA-pHEMA combination. Several

morerecentstudiesexaminedtheuseofnanomaterial-laden

hydrogel contact lenses to achieve controlled drug release

phenomena.[20–23] Nevertheless, a nanomaterial-laden con-

tact lens drug delivery system still faces substantial

challenges. Theobvious challenge is thatwith this controlled

releasemechanism the duration of the therapeutic window

is also prolonged, resulting in the patient having towear the

lenses for a longer period of time, potentially inducing

discomfort. Another challenge is that the diffusional-based

drug release mechanism still causes some of the drugs to be

released in the pre-lens tear film, as opposed to the post-lens

tear film (i.e., between the cornea and the lens), which are

also exposed to the same clearance mechanisms that occur

with topical administration. Lastly, the nanomaterials that

allow a slow release mechanism may also trap the drugs

permanently in the hybrid hydrogelmatrix, which is shown

inPLGA-pHEMAlayers:onlyabout10%ofthetotaldrugfrom

the contact lens was released during the sustained release

phase.[19] This implies that the drug shelf-life must be long

enough so that an efficient amount of drugwill be absorbed

by the cornea before losing its therapeutic efficacy. Finally,

the incorporation of nanomaterials into a contact lensmust

also not compromise key properties of the lens, such as

biocompatibility, modulus (or stiffness), transparency,

comfort, and wettability. Despite these issues, much

progress has been made in utilizing contact lenses as drug

delivery devices. With the advent of nanomaterials, contact

lenses are potentially one of the more convenient ways of

delivering ocular drugs.

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4. Nanomaterials in Ocular Drug Delivery

Much researchhasbeen carried out onusingdifferent types

of nanomaterials for the ophthalmic delivery of drugs.

Sahoo et al. have outlined threemajor goals for ocular drug

delivery nanocarriers: (i) enhancing drug permeation,

(ii) controlling the release mechanisms of drugs, and

(ii) modifying the surfaces of the nanocarriers with specific

targeting moieties.[24] Due to the small size of these

nanocarriers, the permeability of these drug carriers

through the vitreous barrier is greatly enhanced, which

in turn improves the delivery rate of the drugs to the

posterior tissues.Moreover,with themucoadhesiveproper-

ties exhibited by certain types of nanoparticles (NPs), drug

carrier retention may be significantly prolonged in the

targeted tissues. The nanocarrier-drug complex can be

administrated as eyedrop solutions, requiring less frequent

administration due to the higher retention of the drugs,

reducing the cost of administration and increasing patient

compliance. Zimmer and Kreuter have suggested that the

sizes of administered particles for ophthalmic applications

must be less than 10mm in order to avoid the sensation of

scratching upon administration.[25] The potential advan-

tages of using NPs for ocular drug delivery have been

reviewed elsewhere.[26]

The field of ocular drug delivery has been significantly

impacted in the past decade by advances in technology,

especially the development of nanostructured drug car-

riers. It was proposed that microspheres and NPs used for

the encapsulation of drugs would enhance the overall

performance of ocular drug delivery systems.[25] The

application of nanotechnology in the field of ocular drug

delivery has been extensively reviewed by several groups.

Gaudana et al. have highlighted recent advances in

nanotechnology applications for ocular drug delivery,

listing numerous nanostructure carriers as potential ocular

drug carriers.[6] Ludwig has discussed the use of mucoad-

hesive polymer-based nanostructures for the ophthalmic

delivery of drugs, reporting the enhancement of targeting,

and retention of the drugs at the tissue site of interest, such

as the corneal surface.[27]Nagarwal et al. have focusedmore

on polymer-based NPs, exploiting the application of the

block copolymer micelles in the field of ocular drug

delivery.[2]

5. Nanomaterial-Based OphthalmicFormulations Currently in the ClinicalStages

The studies discussed thus far have focused on the initial

proof-of-concept stage of nanomaterials in the field of

ocular drug delivery.



Table 1 below summarizes the progress of nanomaterial-

based ocular drug delivery system in the clinical stages. The

past few decades have seen a significant increase in the

number of journal articles published dealing with devel-

oping advanced ocular drug delivery systems.Among these

delivery systems, eye-drop formulations incorporatedwith

various drug release-controlling excipients (i.e., polycarbo-

phil) are currently available in the market.[28] A number of

products in the form of intravitreal implants, inserts, or

puctal plugs in the micro- or milli-scale are also currently

being developed by various pharmaceutical companies.[28]

Although numerous nanomaterial-based ocular drug

delivery systems have already progressed onto preclinical

studies (i.e. in vivo animal studies) to characterize their

pharmacokinetic properties in a physiological environ-

ment, very few have progressed to full clinical studies.

Hydrogel carriers of timolol showed improved control over

the individual variation of timolol concentration in the

aqueous humor among human patients, compared to the

pure drug suspension.[29] The lowered variation in drug

concentration reduces theprobabilityofhaving insufficient

local drug concentration, and it also reduces the risk of toxic

effects causedbythepresenceofexcessiveamountsofdrug.

Another interesting delivery method using trans-scleral

iontophoresis was also studied in human patients.[30]

Iontophoresis uses a small electric current to deliver

charged therapeutic agents across biological membranes,

and it has been extensively studied in ocular drug delivery

as it overcomes issues relating to the various ocular

barriers.[16,31–35] The hydrogel-iontophoresis delivery

method in a randomized human study demonstrated that

a total charge of less than60mAminwerewell toleratedby

patients, rendering itself as a promising ocular drug

delivery method for targeting both anterior and posterior

segments of the eye.

In addition to hydrogel ophthalmic delivery systems,

incorporation of ophthalmic drugs with CD has shown

efficacy in lowering IOP in human patients.[36,37] To-date,

evaluations of nanomaterials such as micelles, liposomes/

niosomes, and dendrimers are currently limited to pre-

clinical animal studies. However, these nanomaterials are

also expected to expand to human clinical phase studies in

the near future, as more preclinical studies demonstrate

their enhanced pharmacokinetic properties.

6. Recent Developments of Nanomaterialsin Ophthalmic Formulations

6.1. Polymeric Micelles

Polymericmicelles are core/shell-structuredNPs formed by

the self-assembly of amphiphilic copolymers. Polymeric

micelles have been investigated extensively in the field of

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Table 1. List of preclinical and clinical studies using nanomaterials in ocular drug delivery system.

Nanomaterial Drug Formulation Administration Treatment Clinical

stage

Ref.

microspheres triamcinolone

acetonide

PLGA (RETAAC) intravitreal

injection

diabetic macular

edema

launched [96]

micelles dexamethasone NIPAAM-VP-MAA eye-drop inflammation preclinical [97]

dexamethasone Pluronic F127/chitosan eye-drop ocular hypertension preclinical [98]

cyclosporin A MPEG-hexPLA eye-drop dry eye,

autoimmune

uveitis

preclinical [99]

dexamethasone PHEA-PEG eye-drop ocular hypertension preclinical [62]

hydrogels timolol topical ocular hypertension randomized

human

[29]

transceral

iontophoresis

randomized

human

[30]

liposomes flurbiprofen steeric acidþ castor oil eye-drop inflammation preclinical [100]

ciprofloxacin

HCl

chitosan-coated

liposomes

eye-drop conjunctivitis preclinical [101]

fluconazole liposomes eye-drop fungal infection preclinical [102]

ciprofloxacin

HCl

chitosan-coated

liposomes

eye-drop bacterial growth of

P. aeruginosa

preclinical [103]

bevacizumab liposomes intravitreal

injection

ocular neovascular

activity

preclinical [104]

verteporfin liposomes (Visudyne) intravitreal

injection

classic subfoveal

choroidal

neovascularization

launched [28]

dendrimers pilocarpine

nitrate &

tropicamide

PAMAM eye-drop myosis and

mydriasis

preclinical [83]

carteolol phosphorus-containing

dendrimers

eye-drop glaucoma preclinical [86]

cyclodextrins methazolamide HPbCD and HPMC eye-drop ocular hypertension randomized

human

[37]

latanoprost eye-drop open-angle

glaucoma

randomized

human

[36]


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drug delivery as they present numerous advantages.

Polymeric micelles can be fabricated through simple self-

assembly process, usually involving techniques such as

nanoprecipitation, emulsion, or dialysis, in aqueous

medium. In addition, the core/shell structure enables

encapsulation of hydrophobic drugs in its hydrophobic

core. Because the hydrophobic core is shielded by the

hydrophilic corona, the stabilityand thehalf-life of thedrug

are significantly prolonged in the vascular circulation.

Moreover, biodegradable and biocompatible polymers are




selected for formulation of micellar carriers, which would

prevent any adverse effects caused in the physiological

system by the carriers. With these benefits, polymeric

micelles have attracted great interest in the field of drug

delivery over the past few decades,[34,38–43] including drug

delivery for various ocular routes.

Several groups have used polylactide (PLA) or PLGA drug

carriers to enhance the delivery of different types of

drugs.[44–49] PLGA copolymers form micro- or NPs in

aqueous medium by self-assembly phenomena and can

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be used to encapsulate the drugs. However, the challenge

with using PLGA carriers is that they are unstable in

aqueous medium: the ester backbone of the PLGA polymer

isprone tohydrolyticdegradation,whichultimately lowers

the shelf-life of PLGA encapsulated drug complexes. Thus,

many scientists have turned to investigating copolymers

withhydrophilic chains, suchaspoly(ethylene glycol) (PEG)

or poly(ethylene oxide) (PEO) in order to increase the

stability of theNPsby shielding thehydrophobic cores from

hydrolytic degradation. In one study, the effect of PEG

versus chitosan surfacemodification on polymericmicelles

was compared in terms of the ability to penetrate and

deliver drugs across the corneal membrane.[50] Chitosan

was electrostatically anchored to the surface of poly(e-caprolactone) (PCL) nanocapsules, whereas the block

copolymer PCL-b-PEGwas synthesized. The results showed

both nanocapsules increased the permeability of encapsu-

lated drugs through the corneal epithelium compared to

free drug suspension, with Chitosan-coated nanocapsules

increasing the amount of drug permeation up to three

fold after 4 h. However, the mechanism of transport

enhancement remains to be completely dissected. A

triblock copolymer poly(ethylene oxide)-block-poly(propyl-

ene oxide)-block-poly(ethylene oxide) (PEO-PPO-PEO, trade

name: Pluronic F127) was suggested by Pepic et al. for

encapsulation and delivery of pilocarpine.[51] The triblock

copolymer is comprised of a central hydrophobic chain

(PPO) with two hydrophilic chains on either side (PEO)

whichwas shown to self-assemble into amicellar structure

in an aqueous environment, with sizes ranging from 16 to

30nmhaving pilocarpine encapsulated. Although the drug

encapsulation efficiency was very low (maximal 1.9wt%),

the authors demonstrated that the miotic response (area

under the curve of miotic response vs. time) using this

micellar solutionofpilocarpinebase showeda64% increase

compared to a standard pilocarpine eye-drop solution.

A PEO-PPO-PEO triblock copolymer was also used in two

other studies. Liaw et al. developed an eye drop solution

containing the polymeric micelles of Pluronic F127 to

deliver DNA plasmids for gene therapy, to increase the

stability of DNA plasmids in vivo.[52] More recently,

Kadam et al. used the micellization of Pluronic F127 in an

aqueous environment to encapsulate the anti-epileptic

drug carbamezapine to increase the water solubility of

the drug.[53]

A stimuli-responsive micellar drug delivery system has

also been developed. A triblock copolymer comprising

N-isopropylacrylamide (NIPAAM), vinylpyrrolidone (VP),

and acrylic acid (AA) were cross-linked with N,N-methyl-

enebis(acrylamide) (MBA) to formNPs.[54] Themicellar NPs

were analyzed for the delivery of the anti-inflammatory

drug Ketorolac. The polymeric micellar system possesses a

unique thermosensitivity, since the lower critical solution

temperature (LCST) of the triblock copolymer was



found near the physiological temperature. Therefore, the

micellar system showed a temperature-dependent release

phenomena, which can be utilized to control the release of

the drugs to specific targeting tissues.

Other types of block copolymers were also exploited by

various research groups. Due to the small sizes and the

stable suspension in aqueous environment, polymeric

micelles have also been injected into the vitreous using

an intravitreal delivery route. Roy et al. were able to

demonstrate intravitreal delivery of antisense oligonucleo-

tides to the retina of a rat using a poly(ethylene oxide)-

block-polyspermine (PEO-b-PSP) carrier to decrease the

fibronectic expression in retinal vascular cells.[55] The block

copolymer formed an effective diameter of 12nmwith the

oligonucleotides embedded in the matrix and the NPs

persisted up to 6 d in the retinal microvessels without

showing any toxic effects. The study proved that the NP

delivery method successfully reduced the expression of

fibronectic mRNA level to 86.7% 2 d after injection, and

down to 46.7% at day 6. An in vivo study carried out by

Bourges et al. demonstrated that NPs injected through an

intravitreal route means showed a tendency to migrate

through the retinal layers andaccumulate in RPE cells. They

observed the presence of theNPs inRPE cells up to 4months

after the initial single intravitreal injection,which provides

a promising long-term drug delivery tool to the posterior

segment of the eye.[56]

Various types of amphiphilic copolymers have also

demonstrated their ability to improve the in vivo bioavail-

ability of the encapsulated drugs. Qu et al. synthesized

chitosan-based amphiphilic copolymer, quaternary ammo-

niumpalmitoylglycolchitosan (GCPQ).[57] The modified

amphiphilic copolymer encapsulated hydrophobic drugs

by forming micellar clusters, and showed encapsulation of

up to 20–200 times more hydrophobic drugs compared to

that of Pluronic block copolymers. Upon both intravenous

injection and topical ocular application of GCPQ with

prednisolone, the bioavailability of prednisolone increased

tenfold compared to a commercial emulsion formulation of

thesamedrug. Shenetal. utilized thiolatedPEGstearateasa

surfactant tomodify the surface of thenanostructured lipid

carrier (NLC) in order to render mucoadhesiveness for the

nanodrug carriers.[58] The mucoadhesion was achieved

by the disulfide linkage between the thiol groups of the

nanocarrier and the mucin particles (Figure 4). When

topically administered to the rabbit eye, the thiolated NLC

improved the drug concentration and the precorneal

retention time of the encapsulated cyclosporine, which

remained in the cul-de-sac for up to 6h. A number of

studies have also focused on using prodrugs for enhanced

penetration through ocular barriers.[59,60] An amphiphilic

prodrug of tilisolol, O-palmitoyltilisolol, was developed by

Kawakami et al. in order to improve the ocular adsorption

of the drug through cornea.[61] Upon topical instillation, the

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Figure 4. Schematic representation of the interaction between the thiolated NLCs andmucus. Reproduced with permission from ref.[58].


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prodrug form of tilisolol showed prolonged retention and

high drug concentration in both tear fluid and cornea

compared to the tilisolol suspension.

Micellar drug carriers have also shown increased ocular

permeability ofvariousdrugs,whencompared to their pure

drug solution forms.[62,63] From these studies, it is evident

that polymeric micellar drug carriers have great potential

not only in improving the drug stability and release

mechanism to prolong the therapeutic activity of the

encapsulated drugs, but they also show promise in

increasing the permeability of the drugs through various

ocular barriers.

6.2. Hydrogels

Hydrogels aredefinedaswater-solublepolymericnetworks

that have the ability to absorb more than 20% of their

weight of water and still main their 3D structure.[64]

Hydrogels have been studied extensively in medicinal

applications, such as tissue engineering and drug delivery,

due to their unique properties.[65] The chemical and

physical properties of hydrogels can be easily modified

simply by changing the choice of polymers, since hydrogels

can be fabricated from any hydrophilic polymer. Hydrogel

networks have been extensively studied as controlled

and sustained drug delivery system since the porosity of

their matrix can be tailored by modifying the cross-

linking density, or using external stimuli such as pH or

temperature, to control the diffusivity of the drugs in the

matrix.


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Barbu et al. fabricated nanoparticulate

hybrid polymeric hydrogels with sizes

ranging from 10 to 70nm, to investigate

the feasibility of incorporating various

ophthalmic drugs.[66] The copolymers

used for fabricating the nano-sized

hydrogels combined chitosan or AA-

functionalized chitosan,whichwas copo-

lymerized with either 2-hydroxyethyl

methacrylate (HEMA), or with NIPAAM

to impart thermosensitivity to the

nanoparticulate system. Chitosan-based

nanomaterials have been widely studied

for diverse applications in medicine due

to their biocompatible, biodegradable,

mucoadhesive, and non-toxic proper-

ties.[67] Chitosan’s mucoadhesive prop-

erty is especially important in topical

ocular drug delivery systems, since this

prolongs the retention of the delivery

system within the mucin layer, further

increasing the duration of drug activity.

The in vitro drug release results demon-

strated that the nanoparticulate system

showed sustained-release phenomena and the release rate

of various drugs depended on the % content of chitosan

materials in the hydrogels. More recent studies have

focused on using in situ gelation properties of some of

the hydrogel materials, to enhance the ocular bioavail-

ability of the drugs and the in vivo drug activity. Pluronic

F127, in addition to forming micellar structures due to its

amphiphilic nature, has been used to fabricate hydrogel

network systems. Due to its temperature sensitive nature,

Pluronic F127 was studied by various groups as an in situ

gelling agent for ocular delivery applications.[68,69] The sol-

gel transition temperature of Pluronic F127 was below the

human physiological temperature of 37 8C. This property

was utilized by preparing a liquid solution of Pluronic F127

with drugs of interest at low temperatures. Subsequently,

upon administration into the physiological environment,

the solution undergoes gelation to create a polymeric

matrix, where the drug is entrapped and released slowly

through the gel by diffusion.

6.3. Liposomes

Liposomes are biocompatible and biodegradable particles

consisting of membrane-like lipid bilayers composed

mostly of phospholipids.[70] Formed by amphiphilic phos-

pholipids, liposomes have hollow spherical structures

(vesicles)withboth lipophilic (lipidbilayer) andhydrophilic

(aqueous compartment) phases. Due to this biphasic

nature, liposomes can encapsulate both hydrophilic and/

or lipophilic therapeutic agents in each compartment. The

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properties of liposomes, such as surface charge, can be

tuned substantially by varying the lipid composition. Since

the sialic acid moieties in the mucous membrane of the

corneal surface is negatively charged, positively charged

liposomesarepreferentiallycapturedat thecorneal surface,

as compared to neutral or negatively charged liposomes.[24]

In addition, a recent study showed that positively charged

liposomes also increased the extent of absorption of

the encapsulated drugs across corneal membranes.[71] To

achieve this characteristic, numerous studies have focused

on coating the liposomal surface with the mucoadhesive

polymer chitosan.

Diebold et al. investigated the cellular uptake effects of

liposome/chitosan nanoparticle (LCS/NP) complexes in the

precorneal moieties. Strong cellular uptake of LCS-NP in

the conjunctiva, and less intense uptake by the corneal

epithelium, suggested that the NPs were first retained by

the mucus layer, and subsequently enter through the

conjunctival cells. They also showed that ocular drug

delivery system LCS-NP complexes showed negligible in

vitro toxicity and acceptable in vivo tolerance.[72] Li et al.

proposed using low-molecular-weight chitosan (LCH) coat-

ing on liposomes and investigated their in vitro and in vivo

properties.[73] The coating of LCH not only modified the

surface to have a positive charge to enhance its interaction

with the mucous membrane of the corneal surface, but

it also showed increased transcorneal penetration of the

LCH-coated liposomes. The effect of surface coating theNPs

subsequently led to prolonged retention of the encapsu-

lated drugs at the corneal surface, and suggested the

potential for using the liposomal carriers as a transcorneal

drug delivery system, to increase bioavailability of the

drugs in the aqueous compartment. However, chitosan has

shown precipitation phenomena near physiological pH,

and therefore, some studies used a modified version of

chitosan to solve the precipitation issue. Wang et al. also

explored using N-trimethylchitosan (TMC)-coated lipo-

somes to deliver coenzymeQ10 to thehuman lens epithelial

cells to protect against oxidative damages.[74] Chitosan

chains were modified to the quaternized derivative TMC

to overcome issues such as precipitation of chitosan at

neutral pH. This study also demonstrated that the TMC-

coated liposomes exhibited excellent corneal permeation,

increasing the permeability coefficient more than two

times in comparison with values obtained from a control

study.

Other studies have used different coating materials on

the liposomes to achieve enhanced pharmacokinetic

properties. Hosny developed ofloxacin-encapsulated lipo-

somes, which were further incorporated into an in situ

thermosensitive hydrogel system composed of chitosan/b-

glycerophosphate, to enhance the transcorneal permeation

of ofloxacin.[75] The liposomal hydrogel system improved

the transcorneal permeability of ofloxacin sevenfold



compared to that of the aqueous solution. In addition,

the drug delivery system ensured steady and prolonged

permeation of the drugs, improving the bioavailability.

Bochotetal. usedaPEGcoatingonthe surfaceofa liposomal

formulation, to sterically stabilize the liposomes.[76] The

liposomal formulation was injected into the vitreous

humor, where the liposomes showed favored biodistribu-

tion at retina-choroid moieties, as compared with non-

target tissues such as the sclera or lens. The administration

of liposome-encapsulated phosphodiester (16-mer oligo-

thymidylate) oligonucleotides into the vitreous humor also

showed sustained release, which offers the prospect that

the liposomes can be used as an intravitreal delivery

system, targeting the retina and choroid, where the

majority of ocular diseases occur. Hironaka et al. studied

the effect of size and rigidity of the liposomes on the

delivery performance of the liposomes to the posterior

segment of the eye.[77] It was shown that rigid liposomes

with size ranges in the nanoscale showed significant

potential as an ocular delivery system, targeting the

posterior segment of the eye.

Despite the recent reports of using liposomal formula-

tions for ocular drug delivery and the fact that they

demonstrated improvements in precorneal retention,

sustained drug release, and transcorneal permeation,

liposomes still face challenges in their limited long-term

structural stability and drug loading capacity due to the

inherent complex nature of their structures.

6.4. Niosomes

Niosomes, a specific type of liposome, are comprised of

amphiphilic non-ionic surfactants which form vesicle

structures. Niosomes, like liposomes, can entrap both

hydrophilic and hydrophobic drugs. Niosomes are gener-

allypreferredoverothervesicular systems for topical ocular

drug delivery systems for several reasons; they are

chemically more stable, are less toxic because of the non-

ionic nature of the surfactants, are easier to handlewithout

special precautions, are able to improve the performance of

thedrugviabetterbioavailabilityandcontrolleddeliveryat

a specific site, and they are also biodegradable, biocompa-

tible, and non-immunogenic.[78,79]

Abdelbary and El-gendy investigated niosomes as a

potential topical ocular drug delivery system for the

antibiotic gentamicin.[78] The in vitro results showed that

the encapsulation efficiency was as high as 92%, and the

encapsulation of gentamicin showed prolonged release

compared to the control. The encapsulation efficiency and

the release rate varied depending on the cholesterol

content, the type of surfactant used, and the presence of

the charge-inducer dicetyl phosphate. An ocular irritancy

test of niosomes demonstrated no sign of redness,

inflammation, or increased tear production, suggesting

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that niosomes can be used as an enhanced and safe topical

ocular drug delivery system. Prabu et al. studied the

feasibility ofusingboth liposomeandniosomesystemsasa

drug delivery system for brimonidine tartrate, to improve

its IOP lowering activity for the treatment of glaucoma.[80]

The vesicle formulations were in the size range of 210–

245nm, with a drug payload up to 42wt%. Although the

vesicular formulations did not show as high an IOP-

lowering activity as that of the marketed formulation of

pure drug solution, they extended the duration of activity

six to eightfold compared to the marketed formulation.

Niosomes coated with the mucoadhesive material

chitosan, were developed by Kaur et al. to investigate its

potential as a drug delivery system for timolol maleate

(TM), which also lowers IOP in the treatment of glau-

coma.[81] The chitosan-coated niosome showed higher and

prolonged corneal permeation of TM into the aqueous

humor compared to the pure drug solution. Consequently,

the IOP lowering effect of the niosomal formulation of

TM was maintained up to 8h, as compared to 1.5 h for

the drug solution.

6.5. Dendrimers

Dendrimers are three-dimensional, highly branched, and

tree-structured macromolecules which have nanoscale

sizes due to their well-organized synthesis strategy. In

addition, because of their highly branched structure, the

surface of the dendritic macromolecules can be easily

functionalized with a variety of desired properties.

Dendrimers can encapsulate hydrophobic drug molecules

since they possess internal empty cavities and open

conformations, for low generation dendrimers. Due to

the specific combination of properties, dendrimers offer

some attractions for drug delivery applications.[82]

One of the most widely studied dendrimers for use as

an ocular drug delivery system is poly(amidoamine)

(PAMAM). Vandamme and Brobeck used PAMAM dendri-

mers to improve ocular residence time.[83] They have

demonstrated that a 0.25wt% PAMAM solution mixture

with pilocarpine prolonged the ocular residence time of

pilocarpine forup to5h,which is comparable toCarbopol (a

commercial bioadhesive polymer for ophthalmic dosage

forms) but without the irritation that was observed with

Carbopol administration. The study also showed that

residence time was longer for dendrimers with hydroxyl

or carboxyl surface groups. Puerarin/PAMAM complexes

were developed by Yao et al. through hydrogen/bond

interactions.[84] Similar to the previous study, they have

demonstrated prolonged ocular residence time of the

puerarin complex formulation, as compared to puerarin

eye drops. It was also reported that although the puerarin/

PAMAM complex did not increase the corneal permeability

coefficient, the physical mixture of cationic G4 PAMAM




dendrimerwith puerarinwas found to enhance the corneal

permeability coefficient and increased the cumulative

amount of puerarin permeating across the cornea. Durairaj

et al. used a complex formation between dendrimeric

polyguanidilyated translocators (DPTs) and gatifloxacin

(GFX) antibiotic to improve the permeation across

sclera-choroid-retinal pigment epithelium (SCRPE) mem-

branes.[85] The complex improved the permeation of GFX

across SCRPE by 40% in 6h. In vivo studies showed that the

topical administration of the complexwas able tomaintain

higher drug concentration for up to 24h, compared to pure

drug solution. Novel phosphorus-containing dendrimers,

with a quaternary ammonium salt as the core and

carboxylic acid terminal groups, have also been synthe-

sized.[86] These cationic dendrimers were able to physically

associate with amino groups of carteolol (an ocular anti-

hypertensive drug) by forming ion pairs. The generation 2

dendrimer/carteolol formulation improved the corneal

penetration by 2.5 times when compared to carteolol

alone. However, the generation 2 dendrimer showed poor

water solubility and therefore the amount of instilled

carteolol was limited.

The ease of surface functionalization and the ability

to encapsulate hydrophobic drugs render dendrimers

an attractive ocular drug delivery system. In some animal

studies however, a vision blurring effect was observed

after the administration of dendrimer on the ocular

surface.[4] This issue must be addressed in future studies

using dendrimers, before proceeding to full clinical trial

studies.

6.6. Cyclodextrins (CDs)

CDs are a family of cyclic oligosaccharides, composed of six

to eight glucose units which have been shown to improve

the pharmacokinetic properties of many drugs, through

the formation of an inclusion complex.[87] The application

of CDs to ophthalmic formulations has been reviewed

extensively over the past decade.[87–89] The complex

inclusion of hydrophobic drugs with CDs can increase the

aqueous solubility of those drugs. Toxicity studies have

shown that orally administered CDs are practically non-

toxic, due to the lackof absorption fromthegastrointestinal

tract.[90]Oneof themostextensively researchedCDsusedas

an ocular drug delivery enhancement is 2-hydroxypropyl-

b-CD (HPbCD), which is modified with a hydroxylpropyl

derivative to increase its water solubility. Topical admin-

istration of CDs have also shown no toxic effects, and eye

drop solutions containing 45% of HPbCD showed no

irritation effects in rabbits.[91] Similar to other types of

nanomaterials described in this paper, CDs also act as a

permeation enhancer at biological barriers such as the

cornea, by increasing the drug retention at the surface of

the corneal epithelium.

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Wanget al. used an inclusion complex of disulfiram (DSF)

and HPbCD in an eye drop formulation to increase the

bioavailability of thedrug across the cornealmembrane.[92]

Along with the addition of the penetration enhancer

hydroxypropylmethylcellulose (HPMC), the eye drop for-

mulation successfully suppressed the cataract effect (i.e.,

lens opacity) for up to 48h in rabbits. Similarly, Zhang et al.

also used HPbCD with the complex inclusion of ketocona-

zole (KET) in a topical eye drop formulation.[93] The

incorporation of HPbCD increased the aqueous solubility

of KET. Compared to the KET suspension, the HPbCD/KET

complex significantly increased the bioavailability of KET;

over 8-fold in the aqueoushumor, and 12-fold in the cornea.

More recently, another group has investigated the complex

between HPbCD and indomethacin and found delayed

release and a high drug stability effect.[94] While showing

no signs of irritation after administration to rabbits, an

HPbCD-indomethacin complex showed significant

improvement in therapeutic efficacy in healing corneal

wounds. Mahmoud et al. developed ionically crosslinked

chitosan/sulfobutylether-b-CD NPs as an ocular drug

delivery system.[95] The NP system showed sustained

release behavior of the encapsulated econazole nitrate.

Furthermore, the incorporationof chitosanonthesurfaceof

the NPs also significantly improved the ocular mucoadhe-

siveness, which supports NPs as being a promising carrier

for controlled ocular drug delivery systems.

7. Outlook

The field of ocular drug delivery has taken a significant

stride forward with the advent of nanotechnology.

Numerous recent studies have focused on using various

types of nanomaterials, such as polymeric micelles,

hydrogels, liposomes, niosomes, dendrimers, and CDs as

drug carriers, to increase the ocular bioavailability of

various therapeutic agents. Topical administration of the

drugs associatedwith thenanomaterials showed sustained

release of the drug which increased the duration of

therapeutic activity, consequently reducing the need for

frequent administration. To-date, demonstrating an

enhancement in the extent of absorption into the vitreous

cavity across corneal membranes, the topical administra-

tionofnanomaterial/drugcomplexes to target theposterior

segment of the eye has yet to be proven to be therapeu-

tically effective compared to intravitreal or periocular

injections. However, due to the invasive nature of

intravitreal and periocular injections, further studies

utilizing nanomaterials to overcome the various ocular

barriers are expected. Although several in vivo studies have

shown that the nanodrug carriers did not induce any signs

of irritation or inflammatory responses, the long-term

effect of these nanomaterials in both the ocular region and



the systemic circulationmust be rigorously analyzed. There

is no doubt that pharmaceutical researchers will continue

improving theperformanceof ocular drugdelivery systems

with thehelpofnanotechnology, toachieve therapeutically

effective, patient-compliant, and low cost systems with

negligible side-effects.

Acknowledgements: This work was financially supported by20/20 Natural Sciences and Engineering Research Council –Ophthalmic Materials Network.

Received: October 21, 2011; Revised: November 11, 2011;Published online: April 17, 2012; DOI: 10.1002/mabi.201100419

Keywords: contact lenses; drug delivery systems; nanomaterials;nanotechnology; ocular drug delivery

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