The document provides an overview of ocular drug delivery systems. It discusses the challenges of delivering drugs to the eye due to protective barriers. It summarizes advances in conventional topical formulations for anterior delivery as well as novel nanoformulations and drug-releasing devices for posterior delivery. The document then describes the anatomy and barriers of the eye, including the cornea, conjunctiva, tear film, and blood-ocular barriers that restrict drug permeation into the eye.

1. Ocular drug delivery systems: An
overview
OVERVIEW OF ARTICLE
Introduction
The major challenge faced by today’s pharmacologist and formulation scientist is ocular drug
delivery. Topical eye drop is the most convenient and patient compliant route of drug
administration, especially for the treatment of anterior segment diseases. Delivery of drugs to
the targeted ocular tissues is restricted by various precorneal, dynamic and static ocular
barriers. Also, therapeutic drug levels are not maintained for longer duration in target tissues.
In the past two decades, ocular drug delivery research acceleratedly advanced towards
developing a novel, safe and patient compliant formulation and drug delivery
devices/techniques, which may surpass these barriers and maintain drug levels in tissues.
Anterior segment drug delivery advances are witnessed by modulation of conventional topical
solutions with permeation and viscosity enhancers. Also, it includes development of
conventional topical formulations such as suspensions, emulsions and ointments. Various
nanoformulations have also been introduced for anterior segment ocular drug delivery.
On the other hand, for posterior ocular delivery, research has been immensely focused towards
development of drug releasing devices and nanoformulations for treating chronic vitreoretinal
diseases. These novel devices and/or formulations may help to surpass ocular barriers and
associated side effects with conventional topical drops. Also, these novel devices and/or
formulations are easy to formulate, no/negligibly irritating, possess high precorneal residence
time, sustain the drug release, and enhance ocular bioavailability of therapeutics.

2. An update of current research advancement in ocular drug delivery necessitates and helps drug
delivery scientists to modulate their think process and develop novel and safe drug delivery
strategies. Current review intends to summarize the existing conventional formulations for
ocular delivery and their advancements followed by current nanotechnology based formulation
developments. Also, recent developments with other ocular drug delivery strategies
employing in situ gels, implants, contact lens and microneedles have been discussed.
In the words of Hughes and Mitra2: “ophthalmic drug delivery is one of the most interesting
and challenging endeavours facing the pharmaceutical scientist...The anatomy, physiology and
biochemistry of the eye render this organ exquisitely impervious to foreign substances...The
challenge to the formulator is to circumvent the protective barriers of the eye without causing
permanent tissue damage...The primitive ophthalmic solutions, suspensions and ointment
dosage forms are clearly no longer sufficient to combat some present virulent diseases...”
Eye is a unique and very valuable organ. This is considered a window hinge. We can enjoy it
and look at the world body. There are many eye diseases that can affect the body and loss of
vision as well. Therefore, many eyes in drug delivery systems are available. They are classified
as traditional and new drug development system. Topical application of drugs to the eye is the
most popular and well-accepted route of administration for the treatment of various eye
disorders. The bioavailability of ophthalmic drugs is, however, very poor due to efficient
protective mechanisms of the eye. Blinking, baseline and reflex lachrymation, and drainage
remove rapidly foreign substances, including drugs, from the surface of the eye [1].
There are many eye ailments which affected to eye and one can loss the eye sight also.
Therefore many ophthalmic drug delivery systems are available. These are classified as
conventional and non-conventional (newer) drug delivery systems. Most commonly available
ophthalmic preparations are eye drops and ointments about 70% of the eye dosage
formulations in market. But these preparations when instilled into the culde-sac are rapidly
drained away from the ocular cavity due to tear flow and lachrymal nasal drainage. Only a small
amount is available for its therapeutic effect resulting in frequent dosing. So overcome to these
problems newer pharmaceutical ophthalmic formulation such as in-situ gel, nanoparticle,
liposome, nanosuspension, microemulsion, intophoresis and ocular inserts have been developed
in last three decades increase the bioavailability of the drug as a sustained and controlled
manner [2-9].

3. Advantages of ocular drug delivery systems
1. Increased accurate dosing. To overcome the side effects of pulsed dosing produced by
conventional systems.
2. To provide sustained and controlled drug delivery.
3. To increase the ocular bioavailability of drug by increasing the corneal contact time. This can
be achieved by effective adherence to corneal surface.
4. To provide targeting within the ocular globe so as to prevent the loss to other ocular tissues.
5. To circumvent the protective barriers like drainage, lacrimation and conjunctival absorption.
6. To provide comfort, better compliance to the patient and to improve therapeutic performance
of drug.
7. To provide better housing of delivery system.
Limitations of ophthalmic drug delivery:
1. Dosage form cannot be terminated during emergency.
2. Interference with vision.
3. Difficulty in placement and removal.
4. Occasional loss during sleep or while rubbing eyes.
Despite these limitations, significant improvements in ocular drug delivery have been made. The
improvements have been with objective of maintaining the drug in the bio-phase for an
extended period. The anatomy, physiology and biochemistry of the eye render this organ
impervious to foreign substances [10].
Anatomy and function of the eye
The eye is a spherical structure with a wall consisting of three layers; the outer sclera, the
middle choroid layer, Ciliary body and iris and the inner nervous tissue layer retina. The sclera is
tough fibrous coating that protects the inner layers. It is white except for the transparent area
at the front, the cornea which allow light to enter the eye. The choroid layer, situated inside the
sclera, contains many blood vessels and is modified at the front of the eye as pigmented iris.
The iris is the coloured part of the eye (in shades of blue, green, brown, hazel, or grey) [11].

4. The structure of the cornea
The cornea is a strong clear transparent bulge located at the front of the eye that conveys
images to the back of the eyes. The front surface of the adult cornea has a radius of
approximately 8mm that covers about one-sixth of the total surface of the eye ball. It is a
vascular tissue to which nutrient and oxygen are supplied via bathing with lachrymal fluid and
aqueous humour as well as from blood vessels that lines the junction between the cornea and
sclera (in fig.1) [12].
The cornea is the main pathway permeation of drug into the eye. It is composed of five layers:
epithelium, Bowman’s layer, stroma, Descemet’s membrane and endothelium [13, 14]. The
epithelium consists of 5 to 6 layers of cells. The corneal thickness is 0.5–0.7 mm and it is
thicker in the central region. The corneal epithelium is the main barrier of drug absorption into
the eye in Comparison to many other epithelial tissues (intestinal, nasal, bronchial, and
tracheal) corneal epithelium is relatively impermeable [15]. The epithelium is squamous
stratified, consisting of 5-6 layer of cells with a total thickness around 50-100 μm and turnover
of about one cell layer per day. The basal cells are packed closely together with a tight junction,
to forming not only an effective barrier to most microorganisms, but also for drug absorption.
Drugs penetrate across the corneal epithelium via the transcellular or paracellular pathway.
Lipophilic drugs prefer the transcellular route and hydrophilic drugs penetrate primarily through
the paracellular pathway which involves passive or altered diffusion through intercellular spaces.
For most topically applied drugs, passive diffusion along their concentration gradient, either
transcellularly or paracellularly, is the main permeation mechanism across the cornea.
Figure1: Structure of the eye

5. The Bowman’s membrane is an acellular homogeneous sheet, about 8-14μm thick situated
between the basement membrane of the epithelium and the stroma. The stroma, or substania
propria, accounts for around 90% of the corneal thickness and contains approximately 85%
water and about 200-250 collagenous lamellae. The lamellae provide physical strength while
permitting optical transparency. The stroma has a relatively open structure and will normally
allow the diffusion of hydrophilic solutes. The descemet’s membrane is secreted by the
endothelium. It lies between the stroma and the endothelium [11, 12].
Conjunctiva
The conjunctiva is involved in the formation and maintenance of the precorneal tear film and in
the protection of the eye. The conjunctiva is a thin transparent membrane, which lines the inner
surface of the eyelids and is reflected onto the globe. The membrane is vascular and moistened
by the tear film. The conjunctiva is composed of an epithelium, a highly vascularised substantia

6. propria, and a submucosa or episclera. The bulbar epithelium consists of 5 to 7 cell layers. The
structure resembles a palisade and not a pavement when compared to the corneal epithelium.
At the surface, epithelial cells are connected by tight junctions, which render the conjunctiva
relatively impermeable. The conjunctival tissue is permeable to molecules up to 20,000 Da,
whereas the cornea is impermeable to molecules larger than 5000 Da. The human conjunctiva
is between 2 and 30 times more permeable to drugs than the cornea and it has been proposed
that loss by this route is a major path for drug clearance. There are 1.5 million globlet cell
present in the conjunctiva with the highest density is in the Inferonasal quadrant (10 goblet
cells/mm2). The highest density found in the children and adults varying with age depended
among the intersujects variability. A significant increase in the number of goblet cells was
reported in the case of vernal conjunctivitis and atopic kerato conjunctivitis but a great variation
in goblet cell density results only in a small difference in tear mucin concentration [14, 15].
Nasolachrymal drainage system
Nasolachrymal drainage system consists of three parts; the secretory system, the distributive
system and the excretory system. The secretory portion is composed of the lacrimal gland that
secreted tears are spread over the ocular surface by the eyelids during blinking. The secretory
system is stimulated by blinking and temperature change due to the tear evaporation and reflux
secretors that have an efferent parasympathetic nerve supply and secrete in response to
physical and emotional stimulation e.g. crying. The distributive system consists of the eyelids
and the tear meniscus around the lid edges of the open eye, which spread tears over the ocular
surface by blinking, thus preventing dry areas from developing. The excretory part of the
Nasolachrymal drainage system consists of the lachrymal puncta, the superior, inferior and
common canaliculi; the lachrymal sac, and the nasochrymal duct. In humans, the two puncta
are the openings of the lachrymal canaliculi and are situated on an elevated area known as the
lachrymal papilla. It is thought that tears are largely absorbed by the mucous membrane that
lines the ducts andthe lachrymal sac; only a small amount reaches the nasal passage [11,14].

7. Figure 2: Schematic diagram of naso-lachrymation drainage system
Tear film
The exposed part of the eye is covered by a thin fluid layer, the so-called precorneal tear film.
The film thickness is reported to be about 3–10 Am depending on the measurement method
used. The resident volume amounts to about 10μl. The osmolality of the tear film equals 310–
350 mOsm/kg in normal eyes and is adjusted by the monovalent and divalent inorganic ions
such as Na+, K+, Cl-, HCO3-, and proteins. The mean pH value of normal tears is about 7.4.
Diurnal patterns of pH changes exist, with a general shift from acid to alkaline during the day.
The buffer capacity of the tears is determined by bicarbonate ions, proteins, and mucins [16,
17]. Tears exhibit a non- Newtonian rheological behaviour. The viscosity is about 3 mPas [13].
The mean surface tension value is about 44 mN/m.
Ocular pharmacokinetics
The main routes of drug administration and elimination from the eye have been shown
schematically in Fig. 3.

8. Fig. 3: Schematic presentation of the ocular structure with the routes of drug kinetics
illustrated. The numbers refer to following processes: 1) transcorneal permeation from the
lacrimal fluid into the anterior chamber, 2) non-corneal drug permeation across the conjunctiva
and sclera into the anterior uvea, 3) drug distribution from the blood stream via blood-aqueous
barrier into the anterior chamber, 4) elimination of drug from the anterior chamber by the
aqueous humor turnover to the trabecular meshwork and Sclemm's canal, 5) drug elimination
from the aqueous humor into the systemic circulation across the blood-aqueous barrier, 6) drug
distribution from the blood into the posterior eye across the blood-retina barrier, 7) intravitreal
drug administration, 8) drug elimination from the vitreous via posterior route across the blood-
retina barrier, and 9) drug elimination from the vitreous via anterior route to the posterior
chamber.
The barriers
Drug loss from the ocular surface
After instillation, the flow of lacrimal fluid removes instilled compounds from the surface of the
eye. Even though the lacrimal turnover rate is only about 1 μl/min the excess volume of the

9. instilled fluid is flown to the nasolacrimal duct rapidly in a couple of minutes [18]. Another
source of non-productive drug removal is its systemic absorption instead of ocular absorption.
Systemic absorption may take place either directly from the conjunctival sac via local blood
capillaries or after the solution flow to the nasal cavity [19,20]. Anyway, most of small
molecular weight drug dose is absorbed into systemic circulation rapidly in few minutes. This
contrasts the low ocular bioavailability of less than 5% [18].
Drug absorption into the systemic circulation decreases the drug concentration in lacrimal fluid
extensively. Therefore, constant drug release from solid delivery system to the tear fluid may
lead only to ocular bioavailability of about 10%, since most of the drug is cleared by the local
systemic absorption anyway [21].
Lacrimal fluid-eye barriers
Corneal epithelium limits drug absorption from the lacrimal fluid into the eye [22]. The corneal
barrier is formed upon maturation of the epithelial cells. They migrate from the limbal region
towards the centre of the cornea and to the apical surface. The most apical corneal epithelial
cells form tight junctions that limit the paracellular drug permeation [23]. Therefore, lipophilic
drugs have typically at least an order of magnitude higher permeability in the cornea than the
hydrophilic drugs [24]. Despite the tightness of the corneal epithelial layer, transcorneal
permeation is the main route of drug entrance from the lacrimal fluid to the aqueous humor
(Fig. 3). In general, the conjunctiva is more leaky epithelium than the cornea and its surface
area is also nearly 20 times greater than that of the cornea [25, 26]. Drug absorption across the
bulbar conjunctiva has gained increasing attention recently, since conjunctiva is also fairly
permeable to the hydrophilic and large molecules [27]. Therefore, it may serve as a route of
absorption for larger bio-organic compounds such as proteins and peptides. Clinically used
drugs are generally small and fairly lipophilic. Thus, the corneal route is currently dominating. In
both membranes, cornea and conjunctiva, principles of passive diffusion have been extensively
investigated, but the role of active transporters is only sparsely studied.
Blood-ocular barriers
The eye is protected from the xenobiotics in the blood stream by blood-ocular barriers. These
barriers have two parts: blood-aqueous barrier and blood-retina barrier.
The anterior blood-eye barrier is composed of the endothelial cells in the uvea. This barrier

10. prevents the access of plasma albumin into the aqueous humor, and limits also the access of
hydrophilic drugs from plasma into the aqueous humor. Inflammation may disrupt the integrity
of this barrier causing the unlimited drug distribution to the anterior chamber. In fact, the
permeability of this barrier is poorly characterised. The posterior barrier between blood stream
and eye is comprised of retinal pigment epithelium (RPE) and the tight walls of retinal capillaries
[22,23]. Unlike retinal capillaries the vasculature of the choroid has extensive blood flow and
leaky walls. Drugs easily gain access to the choroidal extravascular space, but thereafter
distribution into the retina is limited by the RPE and retinal endothelia. Despite its high blood
flow the choroidal blood flow constitutes only a minor fraction of the entire blood flow in the
body. Therefore, without specific targeting systems only a minute fraction of the intravenous or
oral drug dose gains access to the retina and choroid. Unlike blood brain barrier, the blood-eye
barriers have not been characterised in terms of drug transporter and metabolic enzyme
expression. From the pharmacokinetic perspective plenty of basic research is needed before the
nature of blood-eye barriers is understood.
Corneal and Non-Corneal Routes of Absorption
Lacrimal drainage and systemic absorption from the conjunctiva can wash away ophthalmic
drops which are the most common type of ocular drugs. This results in absorption of a small
fraction of the drug. [28,29,30] For topical drugs, small lipophilic molecules are normally
absorbed through the cornea, while large hydrophilic molecules such as proteins/gene based
medicines are absorbed via the conjunctiva and sclera.[31] Of these routes, the mechanical and
chemical barrier functions of the cornea control access of exogenous substances into the eye,
thereby protecting intraocular tissues (Fig. 4).
The human cornea measures approximately 12 mm in diameter and 520 μm in thickness, and
consists of five layers, including the epithelium, basement membrane (Bowman's layer), stroma,
Descemet's membrane and endothelium (Fig. 3).

11. Figure 4: Corneal cellular organization, the cornea consists of various transport limiting layers.
The tightest monolayer is made by outer superficial epithelial cells which display tight junction
complexes. The wing and basal cells exhibit gap junctions. The stroma and Descemet’s
membrane cover the inner endothelial cells which contain macula adherens and are more
permeable.
The human corneal epithelium is a stratified, squamous, non-keratinized epithelium 50 μm in
thickness. It is composed of two to three layers of flattened superficial cells, wing cells, and a
single layer of columnar basal cells which are separated by a 10–20 nm intercellular spaces and
have regular intercommunications. These desmosome-attached cells can communicate via gap
junctions through which small molecules traverse. Tight junctions (zonulae occludens) seal the

12. superficial cells, building a diffusion barrier in the surface of the epithelium. Compared to the
stroma and endothelium, the corneal epithelium represents a rate-limiting barrier which hinders
permeation of hydrophilic drugs and macromolecules. The stroma displays hydrophilic nature
due to an abundant content of hydrated collagen, which prevents diffusion of highly lipophilic
agents. The corneal endothelial monolayer maintains an effective barrier between the stroma
and aqueous humor. [32] Active ion and fluid transport mechanisms in the endothelium are
responsible for maintaining corneal transparency. [33] It has been reported that certain drug
properties such as lipophilicity, molecular weight, charge, and degree of ionization can
significantly influence its passive permeability across the cornea. [34] Of these factors,
lipophilicity plays a key role since transcellular permeation of lipophilic drugs through the cornea
is faster and greater as compared to hydrophilic drugs. This route appears to be the main path
for absorption of topical drugs. Greater molecular size decreases the rate of paracellular
permeation of drugs. [35, 36] Once in the cornea, the drug can diffuse into the aqueous humor
and the anterior segment (Fig. 3). However, local administration of conventional drugs via the
corneal route fails to provide adequate concentrations within the vitreous and retina. [37,38]
The conjunctiva is a mucous membrane consisting of vascularized epithelium (2-3 cell layers
thick) and plays an important role as a protective barrier on the ocular surface since tight
junctions are present on the apical surface of its cells. In fact, the bulbar conjunctiva represents
the first barrier against permeation of topically applied drugs via the non-corneal route, which is
the main intraocular route for entry of macromolecules and hydrophilic substances. Due to
significant loss of drug through systemic circulation, the conjunctival sclera pathway appears to
be a non-efficient path resulting in poor bioavailability. [39] The sclera is about 10 times more
permeable than the cornea and half permeable as the conjunctiva. It is poorly vascularized and
consists mainly of collagen and mucopolysaccharides, through which drugs can diffuse and
enter the posterior segment (uveal tract, retina, choroid, vitreous humor).
Diffusion characteristics of various drugs were studied. Scleral permeability was significantly
higher than that in cornea, and permeability coefficients of the beta-blockers ranked as follows:
propranolol > penbutolol > timolol > nadolol for cornea, and penbutolol > propranolol > timolol
> nadolol for the sclera.

13. Routes of ocular drug delivery
There are several possible routes of drug delivery into the ocular tissues (Fig. 3). The selection
of the route of administration depends primarily on the target tissue. Traditionally topical ocular
and subconjunctival administrations are used for anterior targets and intravitreal administration
for posterior targets. Design of the dosage form can have big influence on the resulting drug
concentrations and on the duration of drug action.
Topical ocular
Typically topical ocular drug administration is accomplished by eye drops, but they have only a
short contact time on the eye surface. The contact, and thereby duration of drug action, can be
prolonged by formulation design (e.g. gels, gelifying formulations, ointments, and inserts) [23].
During the short contact of drug on the corneal surface it partitions to the epithelium and in the
case of lipophilic compounds it remains in the epithelium and is slowly released to the corneal
stroma and further to the anterior chamber [40]. After eye drop administration the peak

14. concentration in the anterior chamber is reached after 20–30 min, but this concentration is
typically two orders of magnitude lower than the instilled concentration even for lipophilic
compounds [21]. From the aqueous humor the drug has an easy access to the iris and ciliary
body, where the drug may bind to melanin. Melanin bound drug may form a reservoir that is
released gradually to the surrounding cells, thereby prolonging the drug activity. Distribution to
the lens is much slower than the distribution to the uvea [22]. Unlike porous uvea, the lens is
tightly packed protein rich structure where drug partitioning takes place slowly. Drug is
eliminated from the aqueous humor by two main mechanisms: by aqueous turnover through
the chamber angle and Sclemm's canal and by the venous blood flow of the anterior uvea [22]
(Fig. 3). The first mechanism has a rate of about 3μl/min and this convective flow is
independent of the drug. Elimination by the uveal blood flow, on the other hand, depends on
the drug's ability to penetrate across the endothelial walls of the vessels. For this reason,
clearance from the anterior chamber is faster for lipophilic than for hydrophilic drugs. Clearance
of lipophilic drugs can be in the range of 20–30 μl/min. In those cases, most of drug elimination
takes place via uveal blood flow. Halflifes of drugs in the anterior chamber are typically short,
about an hour. The volumes of distribution are difficult to determine due to the slow
equilibration of drug in the ocular tissues. The estimates in rabbits range from the volume of
aqueous humor (250 μl) up to 2 ml [23]. In the latter case, the slow drug distribution to the
vitreous is included in the volume of distribution. This distribution is slow, because the lens
prohibits drug access to the vitreous. Flow of aqueous humor from the posterior chamber to the
anterior chamber is another limiting factor. Some part of topically administered drugs may
absorb across the bulbar conjunctiva to the sclera and further to the uvea and posterior
segment (Fig. 3). This is an inefficient process, but may be improved by dosage forms that
release drug constantly to the conjunctival surface. The role of this non-corneal route of
absorption depends on the drug properties. Generally more hydrophilic and larger molecules
may absorb via this route. They have particularly poor penetration across the cornea, and
therefore, the relative contribution of the non-corneal is more eminent. Delivery across the
conjunctiva and further to the posterior segment would be desirable, but unfortunately the
penetration is clinically insignificant.

15. Sub-conjunctival administration.
Traditionally subconjunctival injections have been used to deliver drugs at increased levels to
the uvea. Currently this mode of drug delivery has gained new momentum for various reasons.
The progress in materials sciences and pharmaceutical formulation have provided new exciting
possibilities to develop controlled release formulations to deliver drugs to the posterior segment
and to guide the healing process after surgery (e.g. glaucoma surgery) [41]. Secondly, the
development of new therapies for macular degeneration (antibodies, oligonucleotides) must be
delivered to the retina and choroid [42, 43].
After subconjunctival injection drug must penetrate across sclera which is more permeable than
the cornea. Interestingly the scleral permeability is not dependent on drug lipophilicity [44]. In
this respect it clearly differs from the cornea and conjunctiva. Even more interesting is the
surprisingly high permeability of sclera to the large molecules of even protein size [45]. Thus, it
would seem feasible to deliver drugs across sclera to the choroid. However, delivery to the
retina is more complicated, because in this case the drug must pass across the choroid and
RPE. The role of blood flow is well characterise kinetically but the based on the existing
information, there are good reasons to believe that drugs may be cleared significantly to the
blood stream in the choroid. Pitkänen et al. showed recently that RPEis tighter barrier that
sclera for the permeation of hydrophilic compounds [44]. In the case of small lipophilic drugs
they have similar permeabilities. More complete understanding of the kinetics in sclera, choroid
and RPE should help to develop medications with optimal activity in the selected posterior
target tissues. Combination of the kinetic knowledge and cell selective targeting moieties offer
very interesting possibilities.
Intravitreal administration.
Direct drug administration into the vitreous offers distinct advantage of more straightforward
access to the vitreous and retina (Fig. 3). It should be noted, however, that delivery from the
vitreous to the choroid is more complicated due to the hindrance by the RPE barrier. Small
molecules are able to diffuse rapidly in the vitreous but the mobility of large molecules,
particularly positively charged, is restricted [46]. Likewise, the mobility of the nanoparticles is
highly dependent on the structure. In addition to the diffusive movement convection also plays

16. a role [47]. The convection results from the eye movements.
After intravitreal injection the drug is eliminated by two main routes: anterior and posterior
[22]. All compounds are able to use the anterior route. This means drug diffusion across the
vitreous to the posterior chamber and, thereafter, elimination via aqueous turnover and uveal
blood flow. Posterior elimination takes place by permeation across the posterior bloodeye
barrier. This requires adequate passive permeability (i.e. small molecular size, lipophilicity) or
active transport across these barriers. For these reasons, large molecular weight and water-
solubility tend to prolong the half-life in the vitreous [22].
Drugs can be administered to the vitreous also in controlled release formulations (liposomes,
microspheres, implants) to prolong the drug activity.
Mechanism of controlled sustained drug release into the eye
The corneal absorption represents the major mechanism of absorption for the most
conventional ocular therapeutic entities.
Passive Diffusion is the major mechanism of absorption for nor?erodible ocular insert with
dispersed drug. Controlled release can further regulated by gradual dissolution of solid
dispersed drug within this matrix as a result of inward diffusion of aqueous solution.

17. Corneal barrier limitation for topically administered drug
The existing ocular drug delivery systems are thus fair and in-efficient. The design of ocular
system is undergoing gradual transition from an empirical to rational basis; Interest in the
broad areas of ocular drug delivery has increased in recent years due to an increased
understanding of a number of ocular physiological process and pathological conditions. The
focus of this review is the approaches made towards optimization of ocular delivery systems
1. Improving ocular contact time
2. Enhancing corneal permeability
3. Enhancing site specificity [48]
Ophthalmic drug product may be classified according to route of administration.
1. Topical
2. Intraocular
3. Systemic (oral and venous).
Absorption of drugs in the eye takes place either through corneal or non?corneal route.
Maximum absorption takes place though the cornea, which leads the drug into aqueous humor.
Loss of the administered dose of drug, takes place through spillage and removal by the
naso?lacrimal apparatus. The non corneal route involves the absorption across the sclera and
conjunctiva into the intra ocular tissues.
Drug Absorption and Disposition in the Eye
The pharmacokinetics and constraints of ocular drug absorption have been examined
thoroughly in the literature. [49-58] A pharmacokinetic scheme illustrating the precorneal fluid
dynamics and the distribution/ disposition of pilocarpine in rabbits is presented in Figure 5.

18. Figure 5: Pharmacokinetic Scheme Illustrating the Distribution of Pilocarpine from the Tear
Fluid into the Aqueous Humour (modified from reference 59)
It is common knowledge that the ocular bioavailability of drugs applied topically as eye-drops is
very poor. The absorption of drugs in the eye is severely limited by some protective
mechanisms that ensure the proper functioning of the eye, and by other concomitant factors,
for example:
• Drainage of the instilled solutions;
• Lacrimation and tear turnover;
• Metabolism;
• Tear evaporation;
• Non-productive absorption/adsorption;
• Limited corneal area and poor corneal permeability; and
• Binding by the lacrimal proteins.
The drainage of the administered dose via the nasolacrimal system into the nasopharynx and
the gastrointestinal tract takes place when the volume of fluid in the eye exceeds the normal
lacrimal volume of 7–10 microlitres. Thus, the portion of the instilled dose (one to two drops,
corresponding to 50–100 microlitres) that is not eliminated by spillage from the palpebral
fissure is quickly drained and the contact time of the dose with the absorbing surfaces (cornea
and sclera) is reduced to a maximum of two minutes. The lacrimation and the physiological tear
turnover (16% per minute in humans in normal conditions) can be stimulated and increased by
the instillation even of mildly irritating solutions. The net result is a dilution of the applied
medication and an acceleration of drug loss. It is now definitively established that the rate at
which instilled solutions are removed from the eye varies linearly with instilled volume. In other
words, the larger the instilled volume, the more rapidly the instilled solution is drained from the
precorneal area. Ideally, a high concentration of drug in a minimum drop volume would be
desirable. However, there is a practical limit to the concept of minimum dosage volume.
Droppers delivering small volumes are difficult to design and to produce. In addition, their
practical usefulness could be reduced by the fact that most patients cannot detect the
administration of small volumes.
The conjunctival absorption, which occurs via the vessels of the palpebral and scleral

19. conjunctiva, concurs in reducing the drug available for absorption into the eye. Any instilled
drug that has not been swept away from the precorneal area by the drainage apparatus is
subject to protein binding and to metabolic degradation in the tear film. All of these factors may
result in transcorneal absorption of 1% or less of the drug applied topically as a solution. In
summary, the rate of loss of drug from the eye can be 500 to 700 times greater than the rate
of absorption into the anterior chamber.
Drugs applied topically are potentially available for absorption by the scleral and palpebral
conjunctiva (the so-called ‘non-productive’ absorption). Although direct transscleral access to
some intraocular tissues cannot be excluded, it is well documented that drugs that penetrate
the conjunctiva are rapidly removed from the eye by local circulation and undergo systemic
absorption. This may range, for example, from 65% for dipivalylepinephrine to 74% for
flurbiprofen and 80% for timolol. [60] These effects are frequently not anticipated, recognised
or treated appropriately.
In conclusion, the fluid dynamics in the precorneal area of the eye have a huge effect on ocular
drug absorption and disposition. When the normal fluid dynamics are altered by, for example,
tonicity, pH or irritant drugs or vehicles, the situation becomes more complex. The formulations
of ophthalmic drug products must take into account not only the stability and compatibility of a
drug in a given formulation, but also the influence of that formulation on precorneal fluid
dynamics. The concepts exposed in this section are summarised in Figure 6, which illustrates
the various factors and pathways involved in the ocular disposition of formulations applied
topically to the eye.
Figure 6: Schematic Illustration of the Ocular Disposition of Topically Applied Formulations
Recent advances and challenges in ocular drug delivery system
Recent advances in topical drug delivery have been made that improve ocular drug contact time
and drug delivery, including the development of ointments, gels, liposome formulations and
various sustained and controlled-release substrates, such as the Ocusert, collagen shields and
hydrogel lenses. The development of newer topical delivery systems using polymeric gels,
colloidal systems and cyclodextrins will provide exciting new topical drug therapeutics.[61, 62]
The delivery of therapeutic doses of drugs to the tissues in the posterior segment of the eye,
however, remains a significant challenge.[63]

20. Early approaches
A considerable amount of effort has been made in ophthalmic drug delivery since the 1970s.
The various approaches attempted in the early stages can be divided into two main categories:
bioavailability improvement and controlled release drug delivery. The latter was attempted by
various types of inserts and nanoparticles. After initial investigations, some approaches were
dropped quickly, whereas others were highly successfuland led to marketed products.
Table 1:
Developments and challenges
Solutions and suspensions
Solutions are the pharmaceutical forms most widely used to administer drugs that must be
active on the eye surface or in the eye after passage through the cornea or the conjunctiva.
Solutions also have disadvantages: the very short time the solution stays at the eye surface, its
poor bioavailability (a major portion, i.e., 75% is lost via nasolacrimal drainage), the instability
of the dissolved drug and the necessity of using preservatives. A considerable disadvantage of
using eye drops is the rapid elimination of the solution and their poor bioavailability. The
retention of a solution in the eye is influenced by viscosity, hydrogen ion concentration, the
osmolality and the instilled volume. Extensive work has been done to prolong ocular retention
of drugs in the solution state by enhancing the viscosity or altering the pH of the solution. [64-
70]
Figure 7: Ophthalmic solution.

21. Sol to gel systems
The new concept of producing a gel in situ (e.g., in the cul-de-sac of the eye) was suggested
for the first time in the early 1980s. It is widely accepted that increasing the viscosity of a drug
formulation in the precorneal region leads to an increased bioavailability, due to slower
drainage from the cornea. Several concepts for the in situ gelling systems have been
investigated. These systems can be triggered by pH, temperature or by ion activation.
Middleton and Robinson prepared a sol to gel system with mucoadhesive property to deliver the
steroid fluorometholone to the eye. The formulation gave better release of drug over a long
period of time in the rabbit’s eye as compared to conventional eye drops. [71]
Figure 8: Ophthalmic gel applied to eye.
Sprays
Although not commonly used, some practitioners use mydriatics or cycloplegics alone or in
combination in the form of eye spray. These sprays are used in the eye for dilating the pupil or
for cycloplegics examination.

22. Figure 8: ophthalmic sprays are applied always on closed eyes.
Contact lenses
Contact lenses can absorb water-soluble drugs when soaked in drug solutions. These drug-
saturated contact lenses are placed in the eye for releasing the drug for a long period of time.
The hydrophilic contact lenses can be used to prolong the ocular residence time of the drugs. In
humans, the Bionite lens which was made from hydrophilic polymer (2-hydroxy ethyl
methacrylate) has been shown to produce a greater penetration of fluorescein. [72]
Figure 9: Contact lenses.
Artificial tear inserts
A rod shaped pellet of hydroxy propyl cellulose without preservative is commercially available
(Lacrisert). This device is designed as a sustained release artificial tear for the treatment of dry
eye disorders. It was developed by Merck, Sharp and Dohme in 1981. [73]

23. Figure 10: Artificial tear insert.
Filter paper strips
Sodium fluorescein and rose Bengal dyes are commercially available as drug-impregnated filter
paper strips. These dyes are used diagnostically to disclose corneal injuries and infections such
as herpes simplex and dry eye disorders.
Figure 11: Fluorescein paper strips.
Microemulsion
Due to their intrinsic properties and specific structures, microemulsions are a promising dosage
form for the natural defense of the eye. Indeed, because they are prepared by inexpensive
processes through auto emulsification or supply of energy and can be easily sterilized, they are
stable and have a high capacity of dissolving the drugs. The in vivo results and preliminary
studies on healthy volunteers have shown a delayed effect and an increase in the bioavailability
of the drug. The proposed mechanism is based on the adsorption of the nanodroplets
representing the internal phase of the microemulsions, which constitutes a reservoir of the drug
on the cornea and should then limit their drainage. [74-76]

24. Figure 12: Microemulsion of ocular delivery.
Ocular inserts
Ocular inserts are solid dosage forms and can overcome the disadvantage reported with
traditional ophthalmic systems like aqueous solutions, suspensions and ointments. The ocular
inserts maintain an effective drug concentration in the target tissues. Limited popularity of
ocular inserts has been attributed to psychological factors, such as reluctance of patients to
abandon the traditional liquid and semisolid medications and to occasional therapeutic failures
(e.g., unnoticed expulsions from the eye, membrane rupture, etc.). A number of ocular inserts
were prepared utilizing different techniques to make soluble, erodible, nonerodible and hydrogel
inserts. [77–79] The examples of ocular inserts are given in Table 2.
Figure 13: ocular insert.
Table2: Ocular inserts devices [80–88]
Name Description
Soluble ocular drug
Insert Small oval wafer,composed of soluble copolymers consisting of
actylamide, N-venyl pyrrolidone and ethyl acetate,soften on insertion
New ophthalmic drug
delivery system
Medicated solid polyvinyl alcohol flag that is attached to a paper-
covered with handle. On application, the flag detaches and gradually
dissolves, releasing the drugs

25. Collagen shields Erodible disc consist of cross-link porcine scleral collagen
Ocusert Flat, flexible elliptical insoluble device consisting of two layers,
enclosing a areservior, use commercially to deliver Pilocarpine for 7 days
Minidisc or ocular
therapeutic
system 4-5 mm diameter contoured either hydrophilic or hydrophobic
disc
Lacrisert
Rose-shape device made from Hydroxy propyl cellulose use for the eye
syndrome as an alternative to tears
Bioadhesive
ophthalmic eye insets
Adhesive rods based on a mixture of Hydroxy propyl cellulose, ethyl
cellulose, Poly acrylic acid cellulosephthalate
Dry drops
A preservative free of hydrophilic polymer solution that is freeze dried
on the tip of a soft hydrophobic carrier strip, immediately hydrate in tear
strip
Gelfoam
Slabs of Gelfoam impregnated with a mixture of drug and cetyl ester wax
in chloroform
Collagen shield
Collagen is regarded as one of the most useful biomaterials. The excellent biocompatibility and
safety due to its biological characteristics such as biodegradability and weak antigenecity made
collagen the primary resource in medical applications. Collasomes show promise among drug
delivery systems to the human eye. They are first fabricated from porcine scleral tissue, which
bears a collagen composition similar to that of the human cornea. The shields are hydrated
before they are placed on the eye, having been stored in a dehydrated state. Typically the drug
is loaded into the drug solution for a period of time prior to application. Collagen shields are
designed to be inserted in a physician’s office; they often produce some discomfort and
interfere with vision. Shields are not individually fit for each patient, as are soft contact lenses
and therefore, comfort may be problematic and expulsion of the shield may occur. Kaufman et
al have developed a new drug delivery system- collasomes. [89] They combined collagen pieces
or particles and a viscous vehicle that could be instilled beneath the eyelid, thereby simplifying
application and reducing the blurring of vision. Collasomes were well tolerated; and because the
collagen particles are suspended in carrier vehicles, they could be instilled safely and effectively
by patients in much the same fashion as drops or ointments.

26. Figure 14: collagen shield loaded with drug inserted in eye.
Ocular iontophoresis
Iontophoresis is the process in which direct current drives ions into cells or tissues. When
iontophoresis is used for drug delivery, the ions of importance are charged molecules of the
drug. [90] If the drug molecules carry a positive charge, they are driven into the tissues at the
anode; if negatively charged, at the cathode. Ocular iontophoresis offers a drug delivery system
that is fast, painless and safe; and in most cases, it results in the delivery of a high
concentration of the drug to a specific site. Increased incidence of bacterial keratitis, frequently
resulting in corneal scarring, offers a clinical condition that may benefit from drug delivery by
iontophoresis. Iontophoretic application of antibiotics may enhance their bactericidal activity
and reduce the severity of disease; similar application of anti-inflammatory agents could
prevent or reduce vision threatening side effects. [91-92] But the role of iontophoresis in clinical
ophthalmology remains to be identified.

27. Figure 15: Treatment via ocular ionotophoresis.
Liposomes
Liposomes are phospholipid-lipid vesicles for targeting drugs to the specific sites in the body.
They provide controlled and selective drug delivery and improved bioavailability and their
potential in ocular drug delivery appears greater for lipophilic than hydrophilic compounds.
Liposomes offer the advantage of being completely biodegradable and relatively nontoxic but
are less stable than particulate polymeric drug delivery systems. Liposomes were found to be a
potential delivery system for administration of a number of drugs to the eye. [93-94]
Niosomes
In order to circumvent the limitations of liposomes, such as chemical instability, oxidative
degradation of phospholipids, cost and purity of natural phospholipids, niosomes have been
developed as they are chemically stable compared to liposomes and can entrap both hydrophilic
and hydrophobic drugs. They are nontoxic and do not require special handling techniques.
Mucoadhesive dosage forms
The successful development of newer mucoadhesive dosage forms for ocular delivery still poses
numerable challenges. [95] This approach relies on vehicles containing polymers which will
attach, via noncovalent bonds, to conjunctival mucin. Mucoadhesive polymers are usually
macromolecular hydrocolloids with numerous hydrophilic functional groups such as carboxyl-,
hydroxyl-, amide and sulphate, capable of establishing electrostatic interactions. The
bioadhesive dosage form showed more bioavailability of the drug as compared to conventional
dosage forms. Thermes et al evaluated the effect of polyacrylic acid as a bioadhesive polymer
on the ocular bioavailability of timolol. It was found that polyacrylic acid prolonged the effect of
timolol. The pioneering work of Hui and Robinson illustrated the utilization of bioadhesive
polymers in the enhancement of ocular bioavailability of progesterone. Subsequently, several
natural and synthetic polymers have been screened for their ability to adhere to mucin epithelial
surfaces; however, little attention has been paid to their use in ophthalmic drug delivery. [96]
Nanoparticles and microparticles
Particulate polymeric drug delivery systems include micro and nanoparticles. The upper size
limit for microparticles for ophthalmic administration is about 5-10 mm. Above this size, a
scratching feeling in the eye can result after ocular application. Microspheres and nanoparticles
represent promising drug carriers for ophthalmic application.The binding of the drug depends
on the physicochemical properties of the drugs, as well as of the nano- or micro-particle
polymer. After optimal drug binding to these particles, the drug absorption in the eye is
enhanced significantly in comparison to eye drops. Particulates such as nanoparticles,
nanocapsules, submicron emulsions, nanosuspensions improved the bioavailability of ocularly
applied drugs. [97-99]

28. Nanocarriers for ocular drug delivery.
Ocular penetration enhancer
Typically classical penetration enhancers have a nonspecific action on biological membranes.
They work by reversibly or permanently damaging membranes; therefore, their safety is
questionable. Newer penetration enhancers that have been introduced in ocular drug delivery
recently with the aim of solving these problems are cyclodextrins, 1-Dodecylazacycloheptan-2-
one, Saponin, α-AminoAcid, Pz peptide, etc. Obviously, penetration enhancement has its limit. It
is not possible to increase bioavailability indefinitely by use of penetration enhancement alone.
Other approaches such as increased residence time and inhibition of metabolizing enzymes
should be used in conjunction with penetration enhancement. [100]
Use of hyaluronic acid
The sodium salt of hyaluronic acid (SH) is a high molecular weight biological polymer, made of
repeating disaccharide units of glucuronic acid and N-acetyl-b-glucosamine. In the eye, SH is
present in the vitreous body and, in lower concentrations, the aqueous humor. SH have several
uses in ophthalmic therapy, such as protecting corneal endothelial cells during intraocular
surgery, replacing vitreous humor, acting as a tear substitute in the treatment of dry eye and
increasing the precorneal residence time of various drugs.
Cyclodextrin
The development of an ophthalmic drug delivery system based on cyclodextrins is relatively
recent, occurring in the Patel GM, et al.: Advances and challenges in ocular drug delivery
system early 1990s. Cyclodextrins were introduced in ocular drug formulations initially with the
aim of increasing the solubility of lipophilic drugs in solution. The authors also observed a
decreased toxicity of the drug cyclodextrin complex compared to the usual drug formulation or
the prodrug solution (e.g., Pilocarpine Prodrug). Finally, most authors showed increased corneal
permeability and increased bioavailability of the drug despite the assumption that the
complexes did not penetrate across biological membranes. However, cyclodextrin derivatives
possess their own toxicity and these observations vary depending on the studies. Kanai et al
(1989) tested different combinations of ~-CD and a lipophilic immunosuppressive agent
cyclosporin. They found that the complex of cyclosporin-~-CD resulted in lower corneal toxicity
and penetrated into the cornea 5–10 times more than did the drug in a lipophilic vehicle.[101]
Cheeks et al confirmed these results in their study on the corneal penetration of
cyclosporin.[102] Sasamoto et al, when testing the same cyclosporin-~-cyclodextrin complex to
increase drug solubility, recommended topical ~-cyclodextrin-cyclosporin for treating anterior
uveitis in rats with the same efficacy as topical fluorometholone solution.[103]
Non-aqueous vehicle
A non-aqueous, comfortable vehicle is desired for topical ophthalmic drug delivery because of

29. drug degradation triggered by water or the premature leakage of the drug from the delivery
system in the presence of water. Typically, lipophilic vehicles (that is, mineral oils and vegetable
oils) have been used, but they are poorly accepted by patients due to blurred vision and matted
eyelids. Reconstitution with water prior to use is unacceptable because of cost and patient
compliance issues. Perfluorocarbons or fluorinated silicone liquids have recently been suggested
as good non-aqueous vehicles for topical ophthalmic drug delivery. [104] They are chemically
and biologically inert and have low surface tension, excellent spreading characteristics and
close-to-water refractive indices. Perfluorocarbons have been studied for years as a blood
substitute; minimal systemic toxicity is expected via the topical route. [105]
Oxime and methoxime analogs of β-blockers (soft β-blockers for eye targeting)
Several oxime or methoxime analogs of known β-adrenergic blockers are of interest as potential
antiglaucoma agents. [106,107] They represent an important class of potential drugs developed
using general retro-metabolic drug design principles and can be considered as site-specific
enzyme-activated chemical delivery systems (CDSs).[108] The oxime-type CDS approach
proposed here provides site-specific or site-enhanced delivery through sequential, multi-step
enzymatic and/or chemical transformations [Figure 7]. In the case of eye-targeting CDS, this is
achieved through a targetor (T) moiety that is converted into a biologically active function by
enzymatic reactions that take place primarily, exclusively or at higher activity at the site of
action (i.e., Enz2) as a result of differential distribution of certain enzymes found at the site of
action.

30. Figure 16: Schematic representation of the processes that provide eye targeting for the oxime-
type CDS approach used for eye-targeted delivery of active β-blocker drugs (D)
CONCLUSION
Drug delivery to targeted ocular tissues has been a major challenge to ocular scientist, for
decades. Administration of drug solutions as topical drop with conventional formulations was
associated with certain drawbacks which initiated the introduction of different carrier systems
for ocular delivery. Tremendous efforts are being put into ocular research toward the
development of safe and patient compliant novel drug delivery strategies. Currently,
researchers are thriving hard to improve in vivoperformance of conventional formulations.
On the other hand, advent of nanotechnology, new techniques, devices and their applications in
drug delivery is developing immense interest to ocular scientists. Drug molecules are being
encapsulated into nanosized carrier systems or devices and are being delivered by invasive/non-
invasive or minimally invasive mode of drug administration. Several nanotechnology based
carrier systems are being developed and studied at large such as nanoparticles, liposomes,
nanomicelles, nanosuspensions and dendrimers.
Few of these are commercially manufactured at large scale and are applied clinically.
Nanotechnology is benefiting the patient body by minimizing the drug induced toxicities and
vision loss. Also, these nanocarriers/devices sustain drug release; improve specificity, when
targeting moieties are used, and help to reduce the dosing frequency. However, there is still
need of developing a carrier system which could reach targeted ocular tissue, including back of
the eye tissues, post non-invasive mode of drug administration.
With the current pace of ocular research and efforts being made and put in, it is expected to
result in a topical drop formulation that retains high precorneal residence time, avoids non-
specific drug tissue accumulation and deliver therapeutic drug levels into targeted ocular tissue
(both anterior and posterior). In near future, this delivery system may replace invasive mode of
drug administration to back of the eye such as periocular and intravitreal injection.

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/////////////Keywords: Anatomy and physiology, Cornea, Contact lens, Drug delivery, Eye,
Emulsions, Formulations, Implants, Liposomes, Nanomicelles, Ointments, Retina, Suspensions