Ocular drug delivery systems are designed to administer drugs onto or inside the eye. Conventional systems include eye drops, emulsions, suspensions, and ointments. However, only a small portion of the drug reaches the eye's interior using these methods. Novel nanotechnology-based systems like micelles, nanoparticles, liposomes, and dendrimers can more effectively target internal ocular tissues and increase drug residence in the eye. These novel systems may help improve treatment of diseases affecting the eye's anterior and posterior segments.

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OCULAR DRUG DELIVERY SYSTEM
“Ocular Drug Delivery System are specialized dosage forms designed to be
instilled onto the external surface of the eye (topical), administered inside
(intraocular) or adjacent (periocular) to the eye or used in conjunction with an
ophthalmic device”.
The Novel approach of drug delivery system in which drug can Instilled on the
cul de sac cavity of eye is known has Ocular drug delivery system.
Advantages of ocular drug delivery system
 Possibility of targeting internal ocular tissue through non-corneal routes.
 Administration of an accurate dose in eye.
 Increasing ocular residence, hence improving bioavailability.
 Reduction of systemic side effects and thus reduced adverse effects in case
of topical application.
 Absence of preservative.
 Increase in shelf life due to absence of water.
Disadvantages of ocular drug delivery system
 Perceived by patient as foreign body.
 Insertion technique is difficult and expulsion of shields may occur not
individually fit for each patient.
 Movement around the eye.
 Occasional loss during sleep or while rubbing eye .
 Interference with vision.
 Difficulty in placement and removal.
Ideal ophthalmic delivery system
 Prolong contact time with corneal tissue.
 Good corneal penetration.
 Simplicity of instillation for the patient.
 Non irritative and comfortable form.
 Appropriate rheological properties

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Mechanism of ocular drug absorption
There are two types of ocular drug absorption
1) Corneal absorption
2) Non corneal absorption
1) Corneal absorption
 It depends upon the physiochemical properties of drug.
 It only access to small ionic and lipophilic molecules.
 Trans cellular transport: Transport between corneal epithelium and stroma.
Eg: Pilocarpine
2) Non corneal absorption
 Penetration across sclera and conjunctiva into intra ocular tissues.
 Non-productive: Because penetrated drug is absorbed by general circulation.
 Minor pathway.
 Importance for drug with low corneal permeability.
Eg.Insulin

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I.INTRODUCTION
The eye is a complex organ with an unique anatomy and physiology. The
structure of eye can be divided into two main parts: anterior segment and
posterior segment. Anterior segment of the eye occupies approximately one-third
while the remaining portion is occupied by the posterior segment. Tissues such as
cornea, conjunctiva, aqueous humor, iris, ciliary body and lens make up the
anterior portion. Back of the eye or posterior segment of the eye include sclera,
choroid, retinal pigment epithelium, neural retina, optic nerve and vitreous humor.
Fig1: Anatomy of eye
The anterior and posterior segment of eye is affected by various vision threatening
diseases. Diseases affecting anterior segment include, but not limited to
glaucoma, allergic conjunctivitis, anterior uveitis and cataract. While, age-related
macular degeneration (AMD) and diabetic retinopathy are the most prevalent
diseases affecting posterior segment of the eye.

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Topical instillation is the most widely preferred non-invasive route of drug
administration to treat diseases affecting the anterior segment. Conventional
dosage forms such as eye drops account for 90% of the marketed ophthalmic
formulations. The reason may be attributed to ease of administration and patient
compliance. Nonetheless, the ocular bioavailability is very low with topical drop
administration. Numerous anatomical and physiological constraints such as tear
turnover, nasolachrymal drainage, reflex blinking, and ocular static and dynamic
barriers pose a challenge and impede deeper ocular drug permeation. Hence, less
than 5% of topically applied dose reaches to deeper ocular tissues. Also, it is
difficult to achieve therapeutic drug concentration into posterior segment ocular
tissues following topical eye drops instillation because of the above mentioned
barriers. The drug can be delivered to the posterior segment ocular tissues by
different mode of administrations such as intravitreal injections, periocular
injections, and systemic administration. However, small volume of eye compared
to whole body and presence of blood retinal barriers; makes systemic
administration an impractical approach. Intravitreal injection is the most common
and widely recommended route of drug administration to treat posterior ocular
diseases. Though, the need of repeated eye puncture with intravitreal injections
causes several side effects such as endophthalmitis, haemorrhage, retinal
detachment and poor patient tolerance. The trans-scleral drug delivery with
periocular administration route is evolved as an alternative mode of drug delivery
to the posterior ocular tissues. Although trans-scleral delivery is comparatively
easy, less invasive and patient compliant, drug permeation is compromised by
ocular static and dynamic barriers. Ocular barriers to trans-scleral drug delivery
include: static barriers i.e., sclera, choroid and retinal pigment epithelium (RPE),
and dynamic barriers, i.e., lymphatic flow in the conjunctiva and episclera, and
the blood flow in conjunctiva and choroid.
To overcome the ocular drug delivery barriers and improve ocular bioavailability,
various conventional and novel drug delivery systems have been developed such
as emulsion, ointments, suspensions, aqueous gels, nano micelles, nanoparticles,
liposomes, dendrimers, implants, contact lenses, nano suspensions, microneedles,
and in situ thermosensitive gels for the earlier mention ocular diseases. This
review will provide an overview on various conventional and novel ophthalmic

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drug delivery systems developed to deliver drug to diseased ocular tissues for the
treatment of ocular diseases.
II. Routes of Ocular drug administration
The different types of routes of ocular drug administration
1) Topical administration
2) Intra vitreal administration
3) Scleral administration
4) Systemic administration
Fig.2 Routes of Ocular drug delivery system.

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1) Topical administration: It is the most commonly used route of drug
administration for the treatment of anterior segment complications. Posterior
segment drug delivery via topical route suffers from drug loss in the precorneal
area and anterior segment, drug elimination from the anterior chamber by the
canal of Schlemn or via absorption through iris-ciliary body. Enzymatic
metabolism in the anterior chamber limits the entry of intact drug into the
posterior segment tissues. Limited success has been achieved with topical
administration in the area of posterior segment drug delivery.
2) Intra vitreal administration: Intravitreal injections have gained considerable
momentum during the past two decades. This method involves injection of
drug solution directly into vitreous via pars plana using a 30 G needle. Unlike
other routes, intravitreal injection offers higher drug concentrations in vitreous
and retina. Elimination of drugs following intravitreal administration depends
on their molecular weight. Linear and globular shaped molecules (especially
protein and peptide drugs) with molecular weight greater than 40 and 70 kDa
respectively tend to cause longer retention in vitreous humor .
Though intravitreal administration offers high concentrations of drugs in retina,
it is associated with various short term complications such as retinal
detachment, endophthalmitis and intravitreal haemorrhage. Moreover, patients
need to be carefully monitored following intravitreal injections.
3) Scleral administration: Due to its large surface area, easy accessibility
and relatively high permeability to macromolecules, the sclera recently has
become a potential vector for posterior segment drug delivery. Scleral drug
delivery has been attempted by different ways, such as scleral plugs and
implants, sun conjunctival injection, subtenon injection. Trans-scleral
administration of drugs offers a promising therapeutic approach for the treatment
of various posterior segment diseases.
4) Systemic administration: Due to the presence of blood retinal barrier, systemic
administration has achieved a limited success to deliver drugs to the vitreo-
retinal tissues. Only 1-2% of plasma drug concentration is achieved in the
vitreous humor and therefore requires frequent administration to maintain
therapeutic drug level. This route of administration may also result in non-
specific binding of drug to other tissues and cause systemic cytotoxicity.

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III.CONVENTIONAL OCULAR DRUG DELIVERY SYSTEMS
Topical drop instillation into the lower precorneal pocket is a patient compliant
and widely recommended route of drug administration. However, most of the
topically administered dose is lost due to reflux blinking and only 20% (−7 μL)
of instilled dose is retained in the precorneal pocket. Concentration of drug
available in the precorneal area acts as a driving force for its passive diffusion
across cornea. However, for efficient ocular drug delivery with eye drops, high
corneal permeation with longer drug cornea contact time is required. There is a
wide range of ophthalmic products available in the market out of which around
70% of prescriptions include conventional eye drops. The reasons may be due to
ease of bulk scale manufacturing, high patient acceptability, drug product
efficacy, stability and cost effectiveness.
The different types of conventional ocular drug delivery system are.
1) Topical liquid / solution eye drops
2) Emulsion
3) Suspension
4) Ointments
1) Topicalliquid/solution eye drops
Topical drops are the most convenient, safe, immediately active, patient
compliant and non-invasive mode of ocular drug administration. An eye drop
solution provides a pulse drug permeation post topical drop instillation, after
which its concentration rapidly declines. The kinetics of drug concentration
decline may follow an approximate first order. Therefore, to improve drug
contact time, permeation and ocular bioavailability; various additives may be
added to topical eye drops such as viscosity enhancers, permeation enhancers
and cyclodextrins. Viscosity enhancers improve precorneal residence time and
bioavailability upon topical drop administration by enhancing formulation
viscosity. Examples of viscosity enhancers include hydroxy methyl cellulose,
hydroxy ethyl cellulose, sodium carboxy methyl cellulose, hydroxypropyl
methyl cellulose and polyalcohol.

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2) Emulsions
An emulsion based formulation approach offers an advantage to improve both
solubility and bioavailability of drugs. There are two types of emulsions which
are commercially exploited as vehicles for active pharmaceuticals: oil in water
(o/w) and water in oil (w/o) emulsion systems. For ophthalmic drug delivery,
o/w emulsion is common and widely preferred over w/o system. The reasons
include less irritation and better ocular tolerance of o/w emulsion.
Emulsions with lipid additives such as soyabean lecithin, stearylamine were
evaluated as carrier systems for azithromycin to demonstrate better ocular
performance and bioavailability.
3) Suspensions
Suspensions are another class of non-invasive ocular topical drop drug carrier
systems. Suspension may be defined as dispersion of finely divided insoluble
API in an aqueous solvent consisting of a suitable suspending and dispersing
agent. In other words, the carrier solvent system is a saturated solution of API.
Suspension particles retain in precorneal pocket and thereby improve drug
contact time and duration of action relative to drug solution. Duration of drug
action for suspension is particle size dependent. Smaller size particle
replenishes the drug absorbed into ocular tissues from precorneal pocket. While
on the other hand, larger particle size helps retain particles for longer time and
slow drug dissolution. Thus, an optimal particle size is expected to result in
optimum drug activity. Several suspension formulations are marketed
worldwide to treat ocular bacterial infections. TobraDex® suspension is one of
the widely recommended commercial products for subjects responding to
steroid therapy. TobraDex® is a combination product of antibiotic tobramycin
(0.3%), and steroid dexamethasone (0.1%). The major drawback of this
commercial product is high viscosity.
4) Ointments
Ophthalmic ointments are another class of carrier systems developed for topical
application. Ocular ointment comprises of mixture of semisolid and a solid
hydrocarbon (paraffin) that has a melting point at physiological ocular
temperature (34 °C). The choice of hydrocarbon is dependent on
biocompatibility. Ointments help to improve ocular bioavailability and sustain
the drug release.

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IV.NOVEL OCULAR DRUG DELIVERY SYSTEMS
Nanotechnologybasedoculardrug delivery
In a last few decades, many approaches have been utilized for the treatment of
ocular diseases. Nanotechnology based ophthalmic formulations are one of the
approaches which is currently being pursued for both anterior, as well as
posterior segment drug delivery. Nanotechnology based systems with an
appropriate particle size can be designed to ensure low irritation, adequate
bioavailability, and ocular tissue compatibility. Several nanocarriers, such as
nanosuspensions, liposomes, nanomicelles and dendrimers have been developed
for ocular drug delivery .
Fig.3 Nanocarrier
1) Nano micelles
Nanomicelles are the most commonly used carrier systems to formulate
therapeutic agents in to clear aqueous solutions. In general, these nanomicelles
are made with amphiphilic molecules. These molecules may be surfactant or
polymeric in nature.
Currently, tremendous interest is being shown towards development of
nanomicellar formulation based technology for ocular drug delivery. The reasons
may be attributed due to their high drug encapsulation capability, ease of
preparation, small size, and hydrophilic nanomicellar corona generating aqueous

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solution. In addition, micellar formulation can enhance the bioavailability of the
therapeutic drugs in ocular tissues, suggesting better therapeutic outcomes
2) Nanoparticles
This approach is considered mainly for the water soluble drugs.
Nanoparticles are particulate drug delivery systems 10-1000 nm in the size in
which the drug may be dispersed, encapsulated or absorbed.
Nanoparticles for ophthalmic drug delivery were mainly produced by
emulsion polymerization. In this process a poorly soluble monomer is dissolved
the continous phase which may be aqueous or organic. Polymerization is started
by chemical initiation or by irradiation with gamma rays, ultraviolet or visible
light. The emulsifier stabilizes the resulting polymer solution. The materials
mainly used for the preparation of ophthalmic nanoparticles are
polyalkylcyanoacrylates. The pH of the polymerization medium has to be kept
below 3. After polymerization pH may be adjusted to the desired value. The
drugs may be added, before, during or after the polymerization. The polymers
used for the preparation of ophthalmic nanoparticles are rapidly bio-degradable.
Hence the nanoparticles are very promising as targeted drug carriers to inflamed
region of the eye.
3) Liposomes
Liposomes are lipid vesicles with one or more phospholipid bilayers enclosing
an aqueous core . The size of liposomes usually range from 0.08 to 10.00 μm
and based on the size and phospholipid bilayers, liposomes can be classified as
small unilamellar vesicles (10–100 nm), large unilamellar vesicles (100–300
nm) and multilamellar vesicles (contains more than one bilayer).
They can be prepared by sonication of dispersion of phospholipids, reverse
phase evaporation, solvent injection, detergent removal or calcium induced
fusion. Lipophilic drugs are delivered to a greater extent to the ocular system
by these liposomes.
The potential advantages achieved with the liposomes are the control of the rate
of encapsulated drug and protection of the drug from the metabolic enzymes
present at the tear corneal epithelium interface.

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The drawbacks associated with the liposomes in ocular drug delivery are due to
short shelf life, limited loading capacity and obstacles such as sterilization of
the preparation.
4) Nano suspensions
Nano suspensions are colloidal dispersion of submicron drug particles
stabilized by polymers or surfactants. It is emerged as promising strategy for
delivery of hydrophobic drugs. For ocular delivery, it provides several
advantages such as sterilization, ease of eye drop formulation, less irritation,
increase precorneal residence time and enhancement in ocular bioavailability of
drugs which are insoluble in tear fluid. The efficacy of nanosuspensions in
improving ocular bioavailability of glucocorticoids has been demonstrated in
several research studies.
5) Dendrimers
Dendrimers are characterized as nanosized, highly branched, star shaped
polymeric systems. These branched polymeric systems are available in
different molecular weights with terminal end amine, hydroxyl or carboxyl
functional group. The terminal functional group may be utilized to conjugate
targeting moieties. Dendrimers are being employed as carrier systems in drug
delivery. Selection of molecular weight, size, surface charge, molecular
geometry and functional group are critical to deliver drugs. The highly
branched structure of dendrimers allows incorporation of wide range of drugs,
hydrophobic as well as hydrophilic. In ocular drug delivery, few promising
results were reported with these branched polymeric systems .
Poly (amidoamine) (PAMAM) dendrimers is widely employed in ocular drug
delivery. The use of dendrimers could be another option for increasing ocular
residence time and therapy enhancing ocular bioavailability and achieving
better therapeutic outcomes.

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V.OPTHALMIC INSERTS
Ophthalmic inserts are aimed at remaining for a long period of time in front of the
eye. These solid devices are intended to be placed in the conjunctival sac and to
deliver the drug at a comparatively slow rate.
Fig 4: Opthalmic inserts
The advantages of these systems are:
1) Ocular contact time is increased.
2) Accurate dosing is possible.
3) Constant and predictable rate of drug release can be achieved.
4) Systemic absorption can be reduced and side effects can be reduced.
5) Increased shelf life can be achieved Better patient compliance. Targeting to
internal ocular tissues can be done.

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Disadvantages of these systems are:
1) Retention in the eye for the full 7 days.
2) Periodical check of unit.
3) Replacement of contaminated unit.
4) Expensive.
VI.TYPES OF OPTHALMIC INSERT
Some of the ophthalmic inserts are as follows.
1) Non-erodible opthalmic insert
a) Ocusert
b) Contact lens
2) Erodible opthalmic insert
a) Laciserts
b) SODI
c) Minidisc
1) Non-erodible ocular insert
The Non-erodible ocular inserts include
a) Ocusert.
b) Contact lens.
a) Ocusert: Ocusert was one of the earlier ocular inserts in use. The technology
used in this is an insoluble delicate sandwich technology . In ocusert the drug
reservoir is a thin disc of pilocarpine-alginate complex sandwiched between
two transparent discs of micro porous membrane fabricated from ethylene-
vinyl acetate copolymer. The micro porous membranes permit the tear fluid to
penetrate into the drug reservoir compartment to dissolve drug from the
complex.
E.g. Alza-ocusert: In this Pilocarpine molecules are then released at a constant
rate of 20 or 40 μg/h for 4 to 7 days. Used in the management of glaucoma.

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Fig 5: Ocusert
Part Material
Drug Reservoir Pilocarpine
Carrier material Alginic acid
Rate controller Ethylene vinyl acetate
copolymer
Energy Source Conc. Of Pilocarpine
Delivery Portal Copolymer membrane
a) Contact lens: The use of pre-soaked hydrophilic contact lenses was used for
ophthalmic drug delivery. Therapeutic soft lenses are used to aid corneal wound
healing in patients with infection, corneal ulcers, which is characterized by
marked thinning of the cornea. An alternative approach to pre-soaked soft
contact lenses in drug solutions is to incorporate carried out the drug either as a
solution or suspension of solid particles in the monomer mix. The
polymerization is then to carried out fabricate the contact lenses. This technique
is promising longer release up to 180 h as compared to pre-soaked contact
lenses.

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Fig 6: Contact lens
2) Erodible ophthalmic insert
The marketed devices of erodible drug inserts are
a) Laciserts
b) SODI (Soluble Ocular Drug Insert)
c) Minidisc
a) Lacisert: It is a sterile rod shaped device made up of hydroxyl propyl
cellulose without any preservative is used for the treatment of dry eye syndromes.
It weighs 5 mg and measures 12.7 mm in diameter with a length of 3.5 mm.
Lacisert is useful in the treatment of keratitis whose symptoms are difficult to treat
with artificial tear alone. It is inserted into the inferior fornix where it imbibes
water from the conjunctiva and cornea, forms a hydrophilic film which stabilizes
the tear film and hydrates and lubricates the cornea. It dissolves in 24 hours.

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fig 7 : Laciserts
b) SODI: Soluble Ocular Drug Insert is a small oval wafer developed for
cosmonauts who could not use eye drops in weightless conditions. It is sterile thin
film of oval shape made from acrylamide, N-vinylpyrrolidone and ethylacrylate.
It weighs about 15-16 mg.
It is used in the treatment of glaucoma and trachoma. It is inserted into the inferior
cul-de-sac and get wets and softens in 10-15 seconds. After 10-15 min the film
turns into a viscous polymer mass, after 30-60 minutes it turns into polymer
solutions and delivers the drug for about 24 hours.
c) Minidisc: The minidisc consists of a contoured disc with a convex front and
concave back surface in the contact with the eyeball. It is like a miniature contact
lens with a diameter of 4-5mm.

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The minidisc is made up of silicone based prepolymer-α-ψ-bis (4-methacryloxy)
butyl polydimethyl siloxane. Minidisc can be hydrophilic or hydrophobic to
permit extend release of both water soluble and insoluble drugs.
fig 8 : Minidisc

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VII. New Ophthalmic Drug Delivery System
The New Ophthalmic Drug Delivery System (NODDS) is a method of presenting
drugs to the eye within a water soluble drug loaded film. It provides accurate,
reproducible dosing in an easily administered preservative free form.
These systems were developed with two primary objectives:
a) To provide a sterile, preservative-free, water-soluble, drug loaded film to the
eye.
b) It serves as a unit-dose formulation for the delivery of a precise amount of
drug to the ocular surface.
The basic design of NODDS consists of three components- Water soluble, drug-
loaded film (flag) attached via Thin, water soluble membrane film, to Thicker,
water-soluble, handle film. All the three films are made using the same grade of
polyvinyl alcohol (PVA) in aqueous medium, but at three different
concentrations. The NODS is approximately 50 mm in length, 6 mm in width, the
flag (drug loaded film) is semi-circular in shape and has an area of 22 sq mm and
a thickness of 20 μm and a total weight of 500 μg of which 40% can be drug.
On contact with the tear film in the lower conjunctival sac, the membrane quickly
dissolves releasing the flag into the tear film. The flag hydrates allowing diffusion
and absorption of the drug. For easy handling the handle film is sandwiched
between the paper strips before the whole unit is sealed in a moisture free pouch.
By this system an eight fold greater bioavailability was observed compared to the
conventional eye drop.

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VII. Implants
Scleral and vitreal implants are developed for treatment of endophthalmitis.
Implants made from poly lactide/glycolide polymers can result in drug release
over 5-6 month period without the need for replacement.
Retisert and intravitreal implants are able to delivers the drug over a six month
period.
fig 9 : Implants

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VIII. CONCLUSION
Drug delivery to eye has always been a daunting task in the field of
pharmaceutical research due to unique anatomy and physiology of the eye. One of
the major problems encountered by conventional ocular dosageforms include
rapid precorneal drug loss due to nasolacrimal drainage, tear turnover and drug
dilution resulting in poorbioavailability. Therefore to improve the ocular drug
bioavailability, considerable amount of research has been focused in developing
controlled drug delivery systems
Controlled drug delivery systems offer many advantages over conventional
dosage forms in terms of improving drug bioavailability, reducing toxicity and
decreasing dosage frequency. The novel advanced delivery systems offer more
protective and effective means of the therapy for the nearly inaccessible diseases
or syndromes of eyes. Progress in the field of ocular drug delivery has been
established recently with controlled loading and sustained release. Hence,
effective drug delivery and targeting is faced by challenges to overcome these
barriers.

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References
[1] URL: Ocular drug delivery system: An overview –NCBI-NIH.
[2] Review Article: “Ocular drug delivery: An update review” by Venkata
Ratnam, Madhavi , Rajesh.ijpbs.com (eISSN: 2230-7605)
[3] Sikandar et al.,Ocular drug delivery system: an overview. Int. J. Phar. Sci.
Res, 2(5): 1168-1175,(2011)
[4] Y.W.Chein , Novel drug delivery systems, second edition.
[5] S.P.Vyas Roop K.Khar ; Controlled Drug Delivery, concepts and advances.