INTRODUCTION

Ocular administration of drug is

primarily associated with the need to
treat ophthalmic diseases.

Eye is the most easily accessible site for
topical administration of a medication.

Ideal ophthalmic drug delivery must
be able to sustain the drug release and
to remain in the vicinity of front of the
eye for prolong period of time.
COMPOSITION OF EYE:


Water - 98%, Solid -1.8%,
Organic element Protein - 0.67%,
sugar - 0.65%, NaCl - 0.66%
Other mineral element sodium,
potassium and ammonia - 0.79%.
EYE AND LACRIMAL DRAINAGE
SYSTEM
ANATOMY OF EYE:

ROUTES OF DRUG DELIVERY IN EYE
MECHANISM OF OCULAR
ABSORPTION
Non- corneal absorption:
Penetration across sclera & conjunctiva into intra
ocular tissues.
Non productive: because penetrated drug is
absorbed by general circulation.
Corneal absorption:
Outer epithelium: rate limiting barrier, with pore
size 60a, only access to small ionic and lipophilic
molecules.
Trans cellular transport: transport between
corneal epithelium and stroma.
FACTORS AFFECTING
INTRAOCULAR BIOAVAILABILITY:
1. Inflow & outflow of lacrimal fluids.
2. Efficient naso-lacrimal drainage.
3. Interaction of drug with proteins of
lacrimal fluid.
4. dilution with tears.
5. Corneal barriers.
6. Active ion transport at cornea.





BARRIERS AVOIDING DRUG DELIVERY

Drug in tear fluid


Ocular absorption




Corneal route Conjunctival and scleral route Systemic absorption
50-100% of dose
Major route- conjunctiva of eye, nose
Minor route- lacrimal drainage system,
pharynx, GIT, aqueous humor

Aqueous humor



Ocular tissue ELIMINATION






OPHTHALMIC DOSAGE FORM
Ophthalmic preparations are sterile
products essentially free from foreign
particles, suitably compounded and
packaged for instillation in to the eye.
The following dosage forms have been
developed to ophthalmic drugs.
Some are in common use, some are
merely experimental, and others are no
longer used.

OCULAR DELIVERY
SYSTEMS
CONVENTIONAL VESICULAR
CONTROL RELEASE PARTICULATE
SOLUTION
SUSPENTION
EMULSION
OINTMENT
INSERT
GELS
IMPLANTS
HYDROGELS
DENDRIMERS
IONTOPORESIS
COLLAGEN SHIELD
POLYMERIC SOLUTIONS
CONTACT LENSES
CYCLODEXRIN
MICROONEEDLE
MICROEMULSIONS
NANO SUSPENSION
ADVANCED
SCLERAL PLUGS
GENE DELIVERY
Si RNA
STEM CELL
ECT
MICROPARTICLES
NANOPARTICLES
LIPOSOMES
NIOSOMES
DISCOMES
PHARMACOSOMES
SELECTED TYPES OF
OCDDS:
1. Aqueous eye drops
2. Oily eye drops


3. Eye ointments

4. Eye lotions


5. Paper strips

6. Ocuserts

7. Hydro gel contact lenses

8. Collagen shields

9. Ophthalmic rods
ADVANTAGES:
They are easily administered by the nurse
They are easily administered by the
patient himself.
They have the quick absorption and
effect.
less visual and systemic side effects.
increased shelf life.
better patient compliance.
DISADVANTAGES:
The very short time the solution
stays at the eye surface.

Its poor bioavailability.

The instability of the dissolved
drug.

The necessity of using preservative.
IDEAL CHARACTERISTICS OF
OCDDS:
Sterility
Isotonicity-e.g.:
1.9% boric acid, 0.9% NaCl
Buffer/pH adjustment
Less drainage tendency
Minimum protein binding

FORMULATION OF OCULAR DRUG
DELIVERY SYSTEM:
Dosage
Form
Advantages Disadvantages
solutions
convenience Rapid precorneal elimination,
non sustained action
suspension Patient compliance, best for
drug with slow dissolution
Drug properties decide
performance loss of both
solutions and suspended
particles
emulsion Prolonged release of drug
from vehicle
Blurred vision, patient non
compliance
ointment Flexibility in drug choice,
improved drug stability
Sticking of eyes lids, blurred
vision, poor patient
compliance
RECENT FORMULATION TRENDS IN OCDDS:

1. CONVENTIONAL DELIVERY SYSTEMS:
Eye Drops:
Drugs which are active at eye or eye surface are widely administered in
the form of Solutions, Emulsion and Suspension.
Various properties of eye drops like hydrogen ion concentration,
osmolality, viscosity and instilled volume can influence retention of a
solution in the eye.
Less than 5 % of the dose is absorbed after topical administration into
the eye.
The dose is mostly absorbed to the systemic blood circulation via the
conjunctival and nasal blood vessels.
Ointment and Gels:
Prolongation of drug contact time
with the external ocular surface can
be achieved using ophthalmic
ointment vehicle but, the major
drawback of this dosage form like,
blurring of vision & matting of eyelids
can limit its use.
Ocuserts and Lacrisert:

Ocular insert (Ocusert) are sterile preparation that
prolong residence time of drug with a controlled release
manner and negligible or less affected by nasolacrimal
damage.
Inserts are available in different varieties depending
upon their composition and applications.
Lacrisert is a sterile rod shaped device for the
treatment of dry eye syndrome and keratitis sicca.
They act by imbibing water from the cornea and
conjunctiva and form a hydrophilic film which lubricates
the cornea.


2) VESICULAR SYSTEM:
Liposomes:

Liposomes are biocompatible and
biodegradable lipid vesicles made
up of natural lipids and about
2510 000 nm in diameter.
They are having an intimate contact with the corneal
and conjunctival surfaces which is desirable for drugs that
are poorly absorbed, the drugs with low partition
coefficient, poor solubility or those with medium to high
molecular weights and thus increases the probability of
ocular drug absorption.


Niosomes and Discomes:
The major limitations of liposomes are chemical instability, oxidative
degradation of phospholipids, cost and purity of natural phospholipids.
To avoid this niosomes are developed as they are chemically stable as
compared to liposomes and can entrap both hydrophobic and hydrophilic
drugs.
They are non toxic and do not require special handling techniques.
Niosomes are nonionic surfactant vesicles that have potential applications in
the delivery of hydrophobic or amphiphilic drugs.
Discomes may act as potential drug delivery carriers as they released drug in
a sustained manner at the ocular site.
Discosomes are giant niosomes (about 20 um size) containing poly-24- oxy
ethylene cholesteryl ether or otherwise known as Solulan 24.
Pharmacosomes: This term is used for pure drug vesicles formed by the
amphiphilic drugs.
The amphiphilic prodrug is converted to pharmacosomes on dilution with water.


Niosomes are microscopic lamellar structures, which are formed on the
admixture of non-ionic surfactant of the alkyl or dialkyl polyglycerol ether
class and cholesterol with subsequent hydration in aqueous media.
Structurally, niosomes are similar to liposomes, in that they are also made
up of a bilayer. However, the bilayer in the case of niosomes is made up of
non-ionic surface active agents rather than phospholipids as seen in the case
of liposomes.

Non ionic surface active agent
phospholipid
Hydrophilic drugs in aqueous
region encapsulated
Lipophilic drugs located in
the hydrophobic lamella
NIOSOME Vs LIPOSOME
3) CONTROL DELIVERY SYSTEMS:

1. Implants:
For chronic ocular diseases like cytomegalovirus (CMV) retinitis, implants
are effective drug delivery system. Earlier non biodegradable polymers
were used but they needed surgical procedures for insertion and removal.
Presently biodegradable polymers such as Poly Lactic Acid (PLA) are
safe and effective to deliver drugs in the vitreous cavity and show no toxic
signs.
2. Iontophoresis:
In Iontophoresis direct current drives ions into cells or tissues. For
iontophoresis the ions of importance should be charged molecules of the
drug.
Positively charged of drug are driven into the tissues at the anode and
vice versa.
Ocular iontophoresis delivery is not only fast, painless and safe but it
can also deliver high concentration of the drug to a specific site.
3. Dendrimer:
Dendrimers can successfully used for different routes of drug
administration and have better water-solubility, bioavailability and
biocompatibility.
4. Microemulsion:
Microemulsion is dispersion of water and oil stabilized using
surfactant and co- surfactant to reduce interfacial tension and
usually characterized by small droplet size (100 nm), higher
thermodynamic stability and clear appearance.
Selection of aqueous phase, organic phase and surfactant/co-
surfactant systems are critical parameters which can affect
stability of the system.
5. Nanosuspensions:
Nanosuspensions have emerged as a promising strategy for the
efficient delivery of hydrophobic drugs because they enhanced
not only the rate and extent of ophthalmic drug absorption but
also the intensity of drug action with significant extended
duration of drug effect.
For commercial preparation of nanosuspensions, techniques
like media milling and high-pressure homogenization have been
used.

6. Microneedle:
Microneedle had shown prominent in vitro penetration
into sclera and rapid dissolution of coating solution after
insertion while in vivo drug level was found to be
significantly higher than the level observed following topical
drug administration like pilocarpine.
7. Mucoadhesive Polymers:
They are basically macromolecular hydrocolloids with
plentiful hydrophilic functional groups, such as hydroxyl,
carboxyl, amide and sulphate having capability for
establishing electrostatic interactions
A mucoadhesive drug formulation for the treatment of
glaucoma was developed using a highly potent beta blocker
drug, levobetaxolol (LB) hydrochloride and partially
neutralized poly acrylic acid (PAA).
4) PARTICULATES (NANOPARTICLES
AND MICROPARTICLES):
The maximum size limit for microparticles
for ophthalmic administration is about
5-10 mm above which a scratching feeling in
the eye can result upon ocular instillation.
That is why microspheres and nanoparticles
are promising drug carriers for ophthalmic
application.
Nanoparticles are prepared using
bioadhesive polymers to provide sustained
effect to the entrapped drugs.

INSERTS

CLASSIFICATION :

1 .NON ERODIBLE INSERTS
i. Ocusert
ii. Contact lens

2 .ERODIBLE INSERTS
i. Lacriserts
ii. SODI
iii. Mindisc

1) NON ERODIBLE INSERTS
OCUSERT:
The Ocusert therapeutic system is a flat, flexible, elliptical device
designed to be placed in the inferior cul-de-sac between the sclera
and the eyelid and to release Pilocarpine continuously at a steady
rate for 7 days.
The device consists of 3 layers..
1. Outer layer - ethylene vinyl acetate copolymer layer.
2. Inner Core - Pilocarpine gelled with alginate main polymer.
3. A retaining ring - of EVA impregnated with titanium di oxide
(diagram)
The ocuserts available in two forms.
Pilo - 20 :- 20 microgram/hour
Pilo 40 :-40 micrograms/hour

ADVANTAGES:
Reduced local side effects and
toxicity.
Around the clock control of IOP.
Improved compliance.
DISADVANTAGES:
Retention in the eye for the full 7
days.
Periodical check of unit.
Replacement of contaminated unit
Expensive.

CONTACT LENSES:

These are circular shaped structures.
Dyes may be added during polymerization.
Drug incorporation depends on whether their structure is
hydrophilic or hydrophobic.
Drug release depends upon :
Amount of drug
Soaking time.
Drug concentration in soaking solution.
ADVANTAGES:
No preservation.
Size and shape
DISADVANTAGES:
Handling and cleaning
Expensive
2) ERODIBLE INSERTS:

The solid inserts absorb the aqueous tear fluid
and gradually erode or disintegrate. The drug is
slowly leached from the hydrophilic matrix.
they quickly lose their solid integrity and are
squeezed out of the eye with eye movement and
blinking.
do not have to be removed at the end of their
use.
Three types :
1. LACRISERTS
2. SODI
3. MINIDISC

LACRISERTS:
Sterile rod shaped device made up of hydroxyl
propyl cellulose without any preservative.
For the treatment of dry eye syndromes
It weighs 5 mg and measures 1.27 mm in
diameter with a length of 3.5 mm.
It is inserted into the inferior fornix.
SODI:
Soluble ocular drug inserts
Small oval wafer
Sterile thin film of oval shape
Weighs 15-16 mg
Use glaucoma
Advantage Single application


MINIDISC:
Countered disc with a convex front and a
concave back surface
Diameter 4 to 5 mm
Composition:
Silicone based prepolymer-alpha-w-dis
(4-methacryloxy)-butyl poly di methyl
siloxane. (M2DX)
M-Methyl a cryloxy butyl functionalities.
D Di methyl siloxane functionalities.
Pilocarpine, chloramphenicol

EVALUATION OF OCDDS:

THICKNESS OF THE FILM:
Measured by dial caliper at different
points and the mean value is calculated.
DRUG CONTENT UNIFORMITY:
The cast film cut at different places and
tested for drug as per monograph.
UNIFORMITY OF WEIGHT:
Here, three patches are weighed.

PERCENTAGE MOISTURE ABSORPTION:
Here ocular films are weighed and placed in
a dessicator containing 100 ml of saturated
solution of aluminium chloride and 79.5%
humidity was maintained.
After three days the ocular films are
reweighed and the percentage moisture
absorbed is calculated using the formula =

% moisture absorbed = Final weight
initial weight/ initial weight x 100
IN VITRO EVALUATION METHODS:

BOTTLE METHOD:
In this, dosage forms are placed in the bottle
containing dissolution medium maintained at specified
temperature and pH.
The bottle is then shaken.
A sample of medium is taken out at appropriate
intervals and analyzed for the drug content.

DIFFUSION METHOD:
Drug solution is placed in the donor compartment and
buffer medium is placed in between donor and receptor
compartment.
Drug diffused in receptor compartment is measured at
various time intervals.
MODIFIED ROTATING BASKET METHOD:
Dosage form is placed in a basket assembly connected to a
stirrer.
The assembly is lowered into a jacketed beaker containing
buffer medium and temperature 37 degrees Centigrade.
Samples are taken at appropriate time intervals and
analyzed for drug content.

MODIFIED ROTATING PADDLE APPARATUS:
Here, dosage form is placed into a diffusion cell which is
placed in the flask of rotating paddle apparatus.
The buffer medium is placed in the flask and paddle is
rotated at 50 rpm.
The entire unit is maintained at 37 degree C.
Aliquots of sample are removed at appropriate time intervals
and analyzed for drug content.



IN- VIVO STUDY:
Here, the dosage form is applied to one eye of
animals and the other eye serves as control.

Then the dosage form is removed carefully at
regular time interval and are analyzed for drug
content.

The drug remaining is subtracted from the
initial drug content, which will give the amount
of the drug absorbed in the eye of animal at
particular time.

After one week of washed period, the
experiment was repeated for two time as before.
ACCELERATED STABILITY STUDIES:

These are carried out to predict the
breakdown that may occur over prolonged
periods of storage at normal shelf condition.
Here, the dosage form is kept at elevated
temperature or humidity or intensity of light,
or oxygen.
Then after regular intervals of time sample
is taken and analyzed for drug content.
From these results, graphical data
treatment is plotted and shelf life and expiry
date are determined.

CONCLUSION:
All approaches improve ocular drug
bioavailability by increasing ocular drug
residence time, diminish side effects due to
systemic absorption and diminishing the
necessary therapeutic amount of drug for
therapeutic response in anterior chamber.
They improve patient compliance by
reducing the frequency of dosing.
They reduce the dose and thereby reduce
the adverse effects of the drug.