International Journal of Research in Pharmaceutical and Biomedical Sciences ISSN: 2229-3701

___________________________________________Review Paper

Basics of Ocular Drug Delivery Systems

P. Tangri*,1, S. Khurana1
1DIT-Faculty of Pharmacy, Mussoorie Diversion Road, Bhagwantpura, Dehradun-248001,
Uttarakhand

ABSTRACT
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
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 cul-de-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. Major improvements are required in each of
the technologies discussed in this review. Some approaches are relatively easy to manufacture, but are limited
in their ability to provide sustained drug release.

KEY WORDS: ocular, drug delivery, ocuserts, ophthalmic.

INTRODUCTION

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
________________________________________
*Address for correspondence:
E-mail: prianshu_tangri@yahoo.co.in
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].
ADVANTAGES OF OCULAR DRUG
DELIVERY SYSTEMS[10-15]
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.

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 International Journal of Research in Pharmaceutical and Biomedical Sciences
OCULAR PHARMACOKINETICS[16-18]
The drug pharmacokinetics from the eye follows
the following paths
 Transcorneal permeation from the lacrimal
fluid into the anterior chamber.
 Non-corneal drug permeation across the
conjunctiva and sclera into the anterior
uvea.
 Drug distribution from the blood stream
via blood-aqueous barrier into the anterior
chamber.
 Elimination of drug from the anterior
chamber by the aqueous humor turnover
to the trabecular meshwork and sclemm's
canal.
 Drug elimination from the aqueous humor
into the systemic circulation across the
blood-aqueous barrier.
 Drug distribution from the blood into the
posterior eye across the blood-retina
barrier.
 Intravitreal drug administration.
 Drug elimination from the vitreous via
posterior route across the blood-retina
barrier.
 Drug elimination from the vitreous via
anterior route to the posterior chamber.
BARRIERS TO OCULAR DRUG DELIVERY
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
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
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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 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
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 International Journal of Research in Pharmaceutical and Biomedical Sciences
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).
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 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
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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.
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
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
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 International Journal of Research in Pharmaceutical and Biomedical Sciences
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.
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
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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 a role [47]. The convection
results from the eye movements.
After intravitreal injection the drug is eliminated by
two main routes: anterior and posterior [48-54]. 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 [55-57]. Drugs can be administered to
the vitreous also in controlled release formulations
(liposomes, microspheres, implants) to prolong the
drug activity.
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
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 International Journal of Research in Pharmaceutical and Biomedical Sciences
sustained and controlled-release substrates, such as
the Ocusert, collagen shields and hydrogel
lenses.[58-60 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]
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 successful and
led to marketed products.
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]
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]
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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.
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]
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]
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.
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]
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,
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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 1.
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.
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.
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[91-92] But the role of iontophoresis in clinical
ophthalmology remains to be identified.
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
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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]
MECHANISM OF DRUG RELEASE
The mechanism of controlled drug release into the
eye is as follows:
A. Diffusion,
B. Osmosis,
C. Bio-erosion.
A. Diffusion:
In the Diffusion mechanism, [100,101] the drug is
released continuously at a controlled rate through
the membrane into the tear fluid. If the insert is
formed of a solid non-erodible body with pores and
dispersed drug. The release of drug can take place
via diffusion through the pores. Controlled release
can be further regulated by gradual dissolution of
solid dispersed drug within this matrix as a result of
inward diffusion of aqueous solutions. In a soluble
device, true dissolution occurs mainly through
polymer swelling. In swelling-controlled devices,
the active agent is homogeneously dispersed in a
glassy polymer. Since glassy polymers are
essentially drug-impermeable, no diffusion through
the dry matrix occurs. When the insert is placed in
the eye, water from the tear fluid begins to
penetrate the matrix, then swelling and
consequently polymer chain relaxation and drug
diffusion take place. The dissolution of the matrix,
which follows the swelling process, depends on
polymer structure: linear amorphous polymers
dissolve much faster than cross-linked or partially
crystalline polymers. Release from these devices
follows in general Fickian 'square root of time'
kinetics; in some instances, however, known as
case II transport or zero order.
B.Osmosis:
In the Osmosis mechanism, [101] the insert
comprises a transverse impermeable elastic
membrane dividing the interior of the insert into a
first compartment and a second compartment; the
first compartment is bounded by a semi-permeable
membrane and the impermeable elastic membrane,
Vol. 2(4) Oct - Dec 2011
ISSN: 2229-3701
and the second compartment is bounded by an
impermeable material and the elastic membrane.
There is a drug release aperture in the impermeable
wall of the insert. The first compartment contains a
solute which cannot pass through the semi-
permeable membrane and the second compartment
provides a reservoir for the drug which again is in
liquid or gel form.
When the insert is placed in the aqueous
environment of the eye, water diffuses into the first
compartment and stretches the elastic membrane to
expand the first compartment and contract the
second compartment so that the drug is forced
through the drug release aperture.
C. Bioerosion:
In the Bioerosion mechanism, [101,102] the
configuration of the body of the insert is constituted
from a matrix of bioerodible material in which the
drug is dispersed. Contact of the insert with tear
fluid results in controlled sustained release of the
drug by bioerosion of the matrix. The drug may be
dispersed uniformly throughout the matrix but it is
believed a more controlled release is obtained if the
drug is superficially concentrated in the matrix.
In truly erodible or E-type devices, the rate of drug
release is controlled by a chemical or enzymatic
hydrolytic reaction that leads to polymer
solubilization, or degradation to smaller, water-
soluble molecules. These polymers, as specified by
Heller, [103] may undergo bulk or surface
hydrolysis. Erodible inserts undergoing surface
hydrolysis can display zero order release kinetics;
provided that the devices maintain a constant
surface geometry and that the drug is poorly water-
soluble.
CONCLUSION
A few new products have been commercialized as a
result of the research into ophthalmic drug delivery.
The performance of these new products, however,
is still far from being perfect. An ideal system
should be able to achieve an effective drug
concentration at the target tissue for an extended
period of time, while minimizing systemic
exposure. In addition, the system should be both
comfortable and easy to use. Patient acceptance
will continue to be emphasized in the design of
future ophthalmic drug delivery systems. Major
improvements are required in each of the
technologies discussed in this review. Some
approaches are relatively easy to manufacture, but
are limited in their ability to provide sustained drug
release. Other approaches are promising with
regard to sustained drug release, but are difficult to
manufacture. Stability is a major issue with
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 International Journal of Research in Pharmaceutical and Biomedical Sciences ISSN: 2229-3701

particulates and liposomes. A reasonable strategy droppable gels and liposomes and nanoparticles
to circumvent the drawbacks of individual coated with bioadhesive polymers.
technologies is to combine technologies. Reported
examples include liposomes and nanoparticles in
Table1: Ocular inserts devices [80–88]

Name Description

Soluble ocular Small oval wafer, composed of soluble copolymers consisting of actylamide, N-venyl pyrrolidone and ethyl acetate,
drug Insert soften on insertion

New Medicated solid polyvinyl alcohol flag that is attached to a paper- covered with handle. On application, the flag
ophthalmic detaches and gradually dissolves, releasing the drugs
drug delivery
system

Collagen Erodible disc consist of cross-link porcine scleral collagen

shields

Ocusert Flat, flexible elliptical insoluble device consisting of two layers, enclosing a areservior, use commercially to deliver
Pilocarpine for 7 days

Minidisc or system 4-5 mm diameter contoured either hydrophilic or hydrophobic disc

ocular
therapeutic
Lacrisert Rose-shape device made from Hydroxy propyl cellulose use for the eye syndrome as an alternative to tears

Bioadhesive Adhesive rods based on a mixture of Hydroxy propyl cellulose, ethyl cellulose, Poly acrylic acid cellulosephthalate
ophthalmic
eye insets

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

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