OCULAR DRUG DELIVERY

SYSTEM
[ODDS]
 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 be non irritant
and it should be able to sustain the drug release and to remain
in the eye for prolong period of time.
 DEFINITION

• They 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 with an
ophthalmic device.
• The most commonly employed ophthalmic dosage forms are
solutions, suspensions, and ointments.
• But these preparations when instilled into the eye are rapidly
drained away from the ocular cavity due to tear flow and
lacrimal nasal drainage
 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%.
 ANATOMY OF EYE
• Diameter 23mm.
• Anterior segment:
• It almost occupies one third of eye
a) Cornea:
• Transparent, devoid of blood vessels and receives nutrients
and oxygen from aqueous humor and tear film.
• It composed of six layers: epithelium, bowman’s layer, stroma,
dua’s layer, descemet’s membrane and endothelium.
b) Conjunctiva:
• Vascularized mucus membrane.
• Helps in hydrating the eye.
c) Iris:
• Consist of pigmented epithelial cells and circular muscles.
• Helps in regulating the pupil size and thus regulating the entry
of light into the eyes.

d) Aqueous humor:
• Fluid present in the anterior segment secreted by ciliary
process into anterior segment.

e) Lens:
• Crystalline and flexible structure enclosed in a capsules.
• Posterior segment
a) Vitreous humor:
• Jelly like substance between the retina and lens
b) Retina:
• Innermost layer of eye.
c) The choroid :
• is the second layer of the eye and lies between the sclera and
the retina. It contains the blood vessels that provide
nourishment to the outer layers of the retina.
d) The sclera :
• The protective outer layer of the eye, referred to as the “white
of the eye” and it maintains the shape of the eye
 OCULAR ABSORPTION

Eg : Pilocarpine Eg: Inulin

GENERAL PATHWAY OF OCULAR
ABSORPTION
 BARRIERS TO OCULAR DRUG
DELIVERY
• it is difficult to achieve relevant therapeutic doses within the
eye.
• it faces multiple obstacles before it reaches its site of action.
• bioavailability of the drug is usually only 1%-7% of the
applied dose.

• The barriers are devided into 2 parts

1. Precorneal constraints
2. Corneal constraints
 PRECORNEAL CONSTRAINTS

a) Solution drainage:
• Eye can accommodate 30µL without blinking.
• Eye dropper deliver volume of 50µL, 70% of administered
dose is expelled by over flow.
• Upon Blinking 10µL residual volume is left (i.e 90% of the
dose expelled)
b) Tear dilution:
• If tears get excessively diluted result in poor bioavailability.
• Factors like pH and tonicity of dosage form cause tear
dilution.
c)Tear turn over:
• If tear destruction is excess more than production ,then tear
become less.
• If tears is less than drug cannot move inside cornea.
d) Conjuctival absorption:
• The drug do not pass through the membrane into aqueous
membrane.
e) Enzymatic metabolism:
• Precorneal and corneal enzymatic metabolism results in loss
of drug entities.
f) Nasolacrimal drainage:

• Causes systemic side effect.

• The drainage rate is much faster than the
ocular absorption rate. So, ocular bioavailability of a drug still
remains challenge.
 CORNEAL CONSTRAINTS

a) cornea:
• Cornea is one of the rate limiting barrier.
• It consits of
• Outer epithelium ( lipophillic)
• Middle stroma ( hydrophillic)
• Inner endothelium ( lipophillic)
• The cornea is a very tight multilayered tissue that is mainly
composed of five sections:
epithelium, bowman’s membrane, stroma, descemet’s membrane
and endothelium.
• the epithelium which acts as the principal barrier.
• These 5-6 layers of columnar epithelial cells with very tight
junctions create high Para cellular resistance .
• It acts as a major barrier to hydrophilic drug transport through
intercellular spaces.
• Stroma , which consists of multiple layers of hexagonally
arranged collagen fibers containing aqueous pores or channels.
• hydrophilic drugs to easily pass through but it acts as a
significant barrier for lipophilic drugs.
• The drug should have the right balance between lipophilicity
and hydrophilicity.
b) Sclera and conjuctiva:

• Non-corneal route by passes the cornea and involves

movement across conjunctiva and sclera.

• This route is important especially for large and hydrophilic

molecules such as peptides, proteins

• Only a small fraction of the dose reaches the vitreous.

c)Blood-ocular barrier
• The blood-ocular barrier normally keeps most drugs out of the
eye.

• These barriers have two parts:

• blood-aqueous humor barrier and
• blood- retina barrier.
1) Blood aqueous humor barrier:
• The anterior blood-ocular barrier is composed of the
endothelial cells in the uvea.
• This barrier limits the access of hydrophilic drugs from plasma
into the aqueous humor.
2) Blood retina barrier:
• The posterior barrier between blood stream and eye is
comprised of retinal pigment epithelium (RPE) and the tight
walls of retinal capillaries
• only a minute fraction of the intravenous or oral drug dose
gains access to the retina.
 NOVEL OCULAR DRUG DELIVERY
SYSTEM
Objectives :
• To prolong the pre ocular retention
• To reduce the frequency of administration
• To provide controlled, continuous drug delivery
• To avoid or minimize the initial drug concentration peak in the
aqueous humour.
APPROACHES TO IMPROVE
OCULAR DRUG DELIVERY
0R
METHODS TO OVERCOME
OCULAR BARRIERS
 VISCOSITY IMPROVER

• Enhances viscosity of the formulation.

• Solution Viscosity inversly proportional Solution Drainage.
• Slows elimination rate from the precorneal area and enhance
contact time.
• Ex: hydrophilic polymers like Methyl cellulose, polyvinyl
alcohols, polyacrylic acids, sodium carboxy methyl cellulose,
carbomer is used.
 USE OF PENETRATION ENHANCERS:
• Act by increasing corneal uptake by modifying the integrity of
the corneal epithelium

• Modes of actions
• By increasing the permeability of the cell membrane.
• Acting mainly on tight junctions.

• Ex: EDTA, sodium caprate etc..,

 OCULAR INSERTS

Classification
1. Non erodible inserts.
• Ocusert
• Contact lens
2. Erodible inserts
• Lacriserts
• SODI
• Minidisc
 NON ERODIBLE INSERTS
OCUSERT
• The Ocusert therapeutic system is a sterile, flat, flexible,
elliptical device consisting of two layers device designed to be
placed in the inferior cul-de-sac between the sclera and the
eyelid
• Release drugs (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
The ocuserts available in two forms.
Pilo – 20 -20 microgram / hour
Pilo – 40 -40 microgram / hour
Use : Chronic glaucoma

Advantages
• Reduced local side effects and toxicity.
• Around the clock control of drug.
• Improved compliance.
Disadvantages
• Retention in the eye for the full 7 days.
• Periodical check of unit.
• Replacement of contaminated unit
• Expensive.
CONTACT LENSES
• can be a way of providing extended release of drugs into the
eye.
• Conventional hydrogel soft contact lenses have the ability to
absorb some drugs and release them into the post lens
lachrymal fluid, minimizing clearance and absorption through
the conjunctiva.
• Their ability to be a drug reservoir strongly depends on the
water content and thickness of the lens, the molecular weight of
the drug, the concentration of the drug loading solution and the
time the lens remains in it.
• Drug incorporation depends upon hydrophilic and hydrophobic
structure.
Advantages
1.No preservation
2.Size & shape
Disadvantages
1.Handling & cleaning
2.Expensive
 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.
• Sterile thin film of oval shape.
• Weighs 15-16 mg.
• Acrylamide, vinyl pyrrolidine, ethylacrylate.
Use – glaucoma.
Advantage – Single application.
MINIDISC
• Countered disc with a convex front and a concave back
surface.
• Diameter – 4 to 5 mm.
• Drug release up to 170hrs
Composition
• Silicone based prepolymer-alpha-w-di (4-methacryloxy)-butyl
poly di methyl siloxane. (M2DX)
• M-Methyl acryloxy butyl functionalities.
• D – Di methyl siloxane functionalities.
• Pilocarpine, chloramphenicol
 IN-SITU GELLING SYSTEM

• it is a drug delivery system which is in a solution form before

the administration in the body but it converts in to a gel form
after the administration
• Due to small changes in specific conditions like pH,
temperature and ionic strength in the environment.
• lastly release the drug slowly under physiological conditions
 MECHANISMS OF GELLING SYSTEM
• In-situ gel formation may be achieved by a number of
mechanisms including
• temperature,
• pH
Temperature triggered in-situ gel system
• which utilizes the temperature sensitive polymers that exist as
a liquid form below its low critical solution temperature
(LCST) and undergoes gelation when the environmental
temperature reaches or is above the LCST
• Polymers: poly(acrylic acid) (PAA) polyacrylamide ( PAAm )
poly( acrylamide -co-butyl methacrylate )
The pH induced in-situ gel system
• contains polymers which possess acidic or alkaline functional
groups within the chain molecule and undergoes a sol-gel
phase transition on change from a low pH to high pH
environment
polymers:
• PAA is converted sol to gel when PH rise from 4.2 to 7.4 .
• At higher pH polymer form bond with mucin which lead to
formation of in situ gel.
• Chitosan sol form at pH 6.2 ,but when pH rise greater than the
6.2 form gel.
• Other polymer are : Hydroxy phthalate latex, Cellulose acetate
phthalate.
 ADVANTAGES

• Increased contact time.

• Improved local bioavailability.
• Reduced dose concentration.
• Reduced dosing frequency.
• Less blurred vision compared to ointments.
• Its production is less complex and thus lowers the investment
and manufacturing cost
THE CORNEAL COLLAGEN SHIELD
• A disposable, short-term therapeutic bandage lens for the
cornea.
• It conforms to the shape of the eye, protects the corneal surface,
and provides lubrication as it dissolves.
• The shields are derived from bovine collagen and are 14.5 mm
in diameter.
• Sterilized by gamma irradiation.
Disadvantages
1.It is not optically clear.
2. The collagen shield causes some discomfort.
Clinical uses
1. Wound healing.
2. Treatment of dry eye.