1. Ocular Drug Delivery System

2. Introduction
The eye is a unique and precious organ. It is
considered as the window of the soul. There are
many eye ailments which affect this organ and
one can loss the eye sight also. Therefore many
ophthalmic drug delivery systems are available.
These are classified as conventional and newer
drug delivery systems. Most commonly available
ophthalmic preparations are eye drops and
ointments, used topically rather systemically.

3. These dosage forms are easy to instill but suffer from
the inherent drawback that the majority of the
medication is immediately diluted in the tear film as
soon as the eye drop solution is instilled into the cul-
de-sac (a short road which is closed off at one end).
And is rapidly drained away from the precorneal
cavity by constant tear flow and lacrimo-nasal
drainage.
Therefore, the target tissue absorbs a very small
fraction of the instilled dose.

4. Limitations of topical and intravitreal route of
administration have challenged scientists to find
alternative mode of administration like periocular
routes. Transporter targeted drug delivery has
generated a great deal of interest in the field because of
its potential to overcome many barriers associated with
current therapy.
Application of nanotechnology has been very promising in
the treatment of a gamut of diseases. Several ocular
drug delivery systems such as microemulsions,
nanosuspensions, nanoparticles, liposomes, niosomes,
dendrimers, implants, and hydrogels are emerged as
novel drug delivery systems for the eye.

5. Anatomy and Routes of Delivery of the eye
Drug delivery to the eye can be broadly classified into anterior and
posterior segments:
Figure 1 : Structure of the eye

6. Anterior segment consists of front one third of
eye that mainly includes pupil, cornea, iris,
ciliary body, aqueous humor, and lens (Fig 1).
The posterior segment consists of the back two
thirds of the eye that includes vitreous humor,
retina, choroid, macula, and optic nerve (Fig 1).

7. Figure 2: Routes of delivery of the eye

8. Periocular route has been considered as the
most promising and efficient route for
administering drugs to posterior eye segment.
Periocular refers to the region surrounding the
eye. It is a broad term which includes
peribulbar, posterior juxtascleral, retrobulbar,
subtenon and subconjunctival routes (Fig 2).
Intravitreal injections have gained considerable
momentum during the past two decades.

9. Various routes and dosage forms used:
• Topical Administration : solutions – eye drops,
ointments, suspensions
• Intravitreal Injections : solutions, suspensions,
implants
• SubTenon Injections : solutions, suspensions,
implants
• Subconjunctival Injections : solutions, suspensions,
implants

10. Drug Delivery to the Front of the Eye (Topical)
Dose in the Eye Absorption via cornea into Aq.
Humor
Drainage and removal
by
Naso-Lacrimal System,
Blinking and tears
Absorption via
Conjunctiva
Ocular
tissues
Systemic
Circulation
Quick Loss

11. Drug Delivery to Front and Back of the Eye

12. Ocular Drug Design and Delivery: Challenges
For the therapeutic treatment of most ocular
problems, topical administration is the preferred
route. But it needs frequent dosing. For systemically
administered drugs, only a very small fraction of the
total dose reach the eye from the general circulatory
system.
Problems with Delivery of Drugs:
 Rapid drain out of the drug from the precorneal cavity by
constant tear flow and lacrimo-nasal drainage.

13.  Blood-retinal barrier (BRB) prevents high
concentrations of drugs passage from the blood
stream.
 Most agents injected into the vitreous are cleared
rapidly and are therefore ineffective.
 Effective dose often toxic.
 Subconjunctival and intravitreal injections carry a
risk of infection.

14. Enhancement in Bioavailability
Topical bioavailability can be improved by
maximizing precorneal drug absorption and
minimizing precorneal drug loss.
1. Viscosity improver:
In order to prolong precorneal residence time and to
improve bioavailability, attempts were made to
increase the viscosity of the formulation.
The viscosity enhancers used were hydrophilic
polymers such as cellulose, polyalcohol and
polyacrylic acid, Sodium carboxy methyl cellulose
etc.

15. 2. Gels :
Gel formation is an extreme case of viscosity
enhancement through the use of viscosity
enhancers. So the dosing frequency can be
decreased to once a day.
Cellulose acetate phthalate dispersion constituted a
micro-reservoir system of high viscosity.
3. Penetration enhancers:
They act by increasing corneal uptake by modifying
the integrity of comeal epithelium.
Chelating agents, preservatives, surfactants and bile
salts were studied as possible penetration
enhancers. But the effort was diminished due to the
local toxicity associated with enhancers.

16. 4. Prodrugs:
Prodrugs enhance corneal drug permeability through
modification of the hydrophilic or lipophilicity of the
drug. The method includes modification of chemical
structure of the drug molecule, thus making it
selective, site specific and a safe ocular drug delivery
system.
Drugs with increased penetrability through prodrug
formulations are - epinehrine, phenylephrine,
timolol, pilocarpine and albuterol.

17. 5. Cyclodextrins:
Cyclodextrins act as carriers by keeping the
hydrophobic drug molecules in solution and
delivering them to the surface of the biological
membrane, where the relatively lipophilic
membrane has a much lower affinity for the
hydrophilic cyclodextrin molecules.
Optimum bioavailability can be achieved when just
enough cyclodextrin (<15%) is added to the
aqueous eye.

18. 6. Bioadhesive polymers:
The bioadhesive polymers adhere to the mucin
coat covering the conjunctiva and the corneal
surfaces of the eye, thus prolonging the
residence time of a drug in the conjunctival sac.
These polymers can be neutral, synthetic or semi
synthetic.
Polyacrylic acid, polycarbophil and hyaluronic
acid are commonly used synthetic polymers.

19. NOVEL OCULAR DRUG DELIVERY
SYSTEMS
One has to understand the physiological and
biochemical factors involved in normal and
pathological conditions for designing a
successful ocular drug delivery system.
An ideal therapy requires selectively targeting of
active agent to various diseases like CNV
(cytomegalovirus), diabetic retinopathy and solid
tumors in the eye.

20. 1. Microemulsions:
Microemulsions are dispersions of water and oil
facilitated by a combination of surfactant and
co-surfactant in a manner to reduce interfacial
tension. These systems are usually
characterized by higher thermodynamic
stability, small droplet size (100 nm) and clear
appearance.
An oil-in-water system consisting of pilocarpine
using lecithin, propylene glycol, PEG 200 as
surfactant/co-surfactants, and isopropyl
myristate as the oil phase has been designed,
which is non-irritating to the rabbit animal
model.

21. 2. Nanosuspensions:
This can be defined as sub-micron colloidal
system which consists of poorly water soluble
drug, suspended in an appropriate dispersion
medium stabilized by surfactants.
Nanosuspenisons usually consist of colloidal
carriers like polymeric resins which are inert in
nature. They help in enhancement of drug
solubility and thus bioavailability.
Unlike microemulsions, they are also popular
because of their non irritant nature.

22. 3. Nanoparticles:
“Nanoparticles are defined as
particles with a diameter of
less than 1 μm, comprising
of various biodegradable or
non biodegradable polymers,
lipids, phospholipids or metals”.
They can be classified as nanospheres or
nanocapsules depending upon whether the drug has
been uniformly dispersed or coated within polymeric
material.
Uptake and distribution of nanoparticles depend on
the size of the nanoparticles. A solid lipid
nanoparticulate system of tobramycin was
developed for topical drug delivery.

23. 4. Liposomes:
Liposomes are lipid vesicles containing
aqueous core which have been widely
exploited in ocular delivery for various drug
molecules. Liposomes containing GCV
(Ganciclovir) were formulated by a reversed
phase evaporation method and in vivo
pharmacokinetic evaluation was performed
in a rabbit model.
Ocular tissue distribution was higher in the
sclera, cornea and vitreous humor from
liposomal formulation.
Acetazolamide was encapsulated in
liposomal formulation for delivery via topical
route.

24. 5. Niosomes:
Niosomes are bilayered structural vesicles
made up of non-ionic surfactant which are
capable of encapsulating both lipophilic and
hydrophilic compounds.
In a recent approach to deliver
cyclopentolate, niosomal formulation was
developed. It released the drug independent
of pH resulting in significant enhancement of
ocular bioavailability
A major advantage of this system was less
systemic drainage because of the large size
and large residence time in the cul-de-sac
due to their disc shape.

25. 6. Dendrimers:
“Dendrimers are macromolecular
compounds made up of a series of branches
around a central core. Their nanosize, ease
of preparation, functionalization and
possibility to attach multiple surface groups
render them suitable alternative vehicle for
ophthalmic drug delivery”.
Major drawbacks associated with these
systems are blurred vision and formation of a
veil leading to vision loss.
Dendrimers consisting of poly (amidoamine)
(PAMAM) have been widely employed in
drug delivery.

26. 7. Cyclodextrins:
“Cyclodextrins (CDs) belong to a group of cyclic
oligosaccharides capable of forming inclusion
complexes with many guest molecules.
Through CD complexation, aqueous solubility of
hydrophobic drugs can be enhanced without
changing their molecular structure and their
intrinsic ability to permeate biological
membranes”.
These complexes have been proven to increase
corneal permeation of drugs like
dexamethasone, cyclosporine and so on.

27. 8. Contact Lenses:
Traditionally used soaked contact lenses
provide a drug release for a few hours.
Current challenges in this mode of drug
delivery are to sustain release for longer
period and also to incorporate sufficient drug
amounts in the lens matrix.
Recently, surfactant loaded polyhydroxy
ethyl methacrylate (p-HEMA) gel has shown
sustained release of cyclosporine-A.
The bioavailability of the formulation was
found better than the topical eye drops.

28. 9. Intraocular Implants:
Implants have been widely employed to extend the
release in ocular fluids and tissues particularly in
the posterior segment.
Implants can be broadly classified into two
categories based on their degradation property:
(a) biodegradable and
(b) non-biodegradable.
With implants, the delivery rate could be modulated
by varying polymer composition. Implants can be in
the form of solid, semi-solid or particulate based
delivery systems.

29. 10. Hydrogel Systems:
The progress has been made
in gel technology to the
development of droppable gel.
They are liquid upon instillation
and undergo phase transition
in the ocular cul-de-sac to form
visco-elastic gel and this provides a response to
environmental changes.
Three methods have been employed to cause
phase transition in the eye surface.
These are change in pH, change in temperature
and ion activation.

30. I. pH: In this method gelling of the solution is triggered by a
change in the pH. CAP latex cross linked polyacrylic acid
and derivatives such as carbomers are used. They are low
viscosity polymeric dispersion in water which undergoes
spontaneous coagulation and gelation after instillation in the
conjunctival cul-de-sac.
II. Temperature: In this method gelling of the solution is
triggered by change in the temperature. Sustained drug
delivery can be achieved by the use of a polymer that
changes from solution to gel at the temperature of the eye.
III. Ionic strength: In this method gelling of the solution
instilled is triggered by the change in the ionic strength.
Example is Gelrite.
Gelrite is a polysaccharide, low acetyl gellan gum, which
forms a clear gel in the presence of mono or divalent
cations. The concentration of sodium in human tears is 2.6
g/l is particularly suitable to cause gelation of the material
when topically installed into the conjunctival sac.

31. 11. Iontophoresis:
Ocular iontophoresis has gained significant
interest recently due to its non-invasive nature
of delivery to both anterior and posterior
segment. It requires a mild electric current
which is applied to enhance ionized drug
penetration into tissue.
This mode of delivery can overcome the
potential side effects associated with intraocular
injections and implants mentioned earlier.
Examples of antibiotics successfully employed
are gentamicin, tobramycin and ciprofloxacin by
this system.

32. 12. Microneedle:
Recently, researchers have attempted microneedle
to deliver drug to posterior segment as an
alternative to topical route. An evaluation of coated
solid metal microneedle to deliver the drug was
carried out both in-vitro and in-vivo.
Microneedle had shown excellent in-vitro
penetration into sclera and rapid dissolution of
coating solution after insertion. In-vivo drug level
was found to be significantly higher than the level
observed following topical drug administration. This
mode of drug delivery was also successful in the
delivery of pilocarpine.

33. 13. Gene Delivery:
Recently, various strategies have been adopted to
deliver nucleic acids to a specific site within the eye.
Designing delivery system for antisense ODNs
(oligodeoxynucleotides), aptamers or siRNAs is a
challenging task for researchers in ocular delivery
field because of high molecular weight, size, surface
charge, solubility of the active drug and intrinsic
complexities associated with the structure of ocular
tissues like retina and cornea.
Recently, FDA has approved Vitravene®, an ODNs
for the treatment of CMV in AIDS patients and
Macugen® (pegaptanib sodium injection) which is
an aptamer for the treatent of “wet” AMD.