634987467930602500

Ocular Drug Delivery System
BY:
Mr V D Ramani
CKPIPSR- Surat
Ocular drug delivery system
2
7/31/2014
The Eye
Human eye consist of :-
1. Sclera,
2. Choroids,
Outer-
Epithelium(lipophilic),
Middle-
Stroma(hydrophilic),
Inner-
Endothelium(lipophilic).
3. Cornea,
4. Cilliary Body-
Secretion of aq.
humor,
5. Lens,
6. Retina,
7. Conjuctiva,
8. Vitreous
Compartment,
9. Lacrimal gland.
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Anatomically cornea consist of five distinct
layer which anterior to posterior are shown.
Drugs gain access into eye by simple
passive diffusion.
The epithelium and endothelium are
cellular and lipophillic.
Stroma represents 90% of thickness of
cornea. It contains 76-80% of water and
rest is collagen fibrils.
Each of three layers were found to
contribute significantly to diffusional
resistance of drugs.
Epithelium is rate limiting barrier for the
hydrophilic drugs whereas stroma is barrier
for lipophilic drugs.
Sclera and conjuctiva are significant for
drug having poor corneal permeability.
Corneal Cross Section
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a = lacrimal gland
b = superior lacrimal
punctum
c = superior lacrimal
canal
d = lacrimal sac
e = inferior lacrimal
punctum
f = inferior lacrimal
canal
g = nasolacrimal canal
The lacrimal glands are paired almond-shaped glands, one for
each eye, that secrete the aqueous layer of the tear film. They
are situated in the upper, outer portion of each orbit.
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Tear drainage
Normal rate of tear secretion : 1.2L/min
Thickness of the tear film: 6.5m

Normal blinking rate:16/min
Normal volume of tears : 7L
Normal tear turnover rate:16%/min
Maximum capacity of cul-de-sac to hold tears
in upright position:30L
Volume delivered by normal dropper:50-75L
Penetration across Sclera & Conjuctiva
into Intra Ocular tissues
Non-Productive: because penetrated drug
is absorbed by general circulation
Outer Epithelium: rate limiting barrier, with
pore size 60 ,
Only access to small ionic & lipohilic
molecules
Trans cellular transport: transport between
corneal epithelium & stroma.
Mechanism of Ocular
Absorption
General Pathway For Ocular Absorption
Ocular drug delivery system 9
Ocular Drug Delivery
Introduction
Ophthalmic preparation
Applied topically to the cornea, or instilled in the space
between the eyeball and lower eyelid

Solution
Dilute with tear and wash away through lacrimal
apparatus
Administer at frequent intervals
Suspension
Longer contact time
Irritation potential due to the particle size of drug
Ointment
Longer contact time and greater storage stability
Producing film over the eye and blurring vision
Controlled delivery system

Release at a constant rate for a long time
Enhanced corneal absorption
Drug with not serious side effect or tolerate by
the patient
Role Of Polymer In ODDS.
Solution Viscosity Solution Drainage.
Polymereric mucoadhesive vehicle: Retained in the eye
due to non-covalent bonding with conjuctival mucine.
Mucine is capable of picking of 40-80 times of weight of
water.
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.
Classification Of Ophthalmic Dosage Form:
A) Based on Root
of Administration
1.Topical Sol
n
: Multiple
Dose container With
Preservatives.
2. Intra-ocular Sol
n:
For
Surgery, Single dose,
Without preservative.

3.Ophthalmic Sol
n
Injections: Intra-ocular
injection, given in eye
tissues, without
preservative.
B) Based on
Physical Form
1. Aqueous Sol
n
.
2. Suspension.
3. Ointments.
4. Gels.
5. Eye Lotions.
6. Solid Inserts.
Ocular indication of controlled-release systems
Indication Drug & Disease
1. Short, topical ocular half-life Heparin for Ligneous disease
2. Small, topical ocular, therapeutic
index
Pilocarpine for chronic open-angle
Glaucoma
3. Systemic side effects Timolol for Glaucoma and cyclosporin A
for graft rejection
4. Need for combination therapy Cromoglycate and corticosteroid for
Asthma and Allergies
5. Drug delivery over a prolonged period Acute corneal infections, Corneal Graft
rejection episodes
6. Long-continued low dosage for
therapy or prophylaxis
Prevention of Corneal Graft Rejection or
Herpetic diseases,
Ocular Control Release System: Ophthalmic Inserts
Definition:- Solid or Semisolid in nature,
- Placed in lower Fornix
- Composed of Polymeric vehicle containing drug.
Desired Criteria For Control Release Ocular Inserts.
Comfort
Ease of
handling
Reprodu
cibility of
release
kinetics
Sterility Stability
Ease of
mfg.

Advantages
1. Accurate dosing.
2. Absence of preservative.
3. Increase in shelf life due to
absence of water.
Limitations
1. Perceived by patient as foreign body.
2. Movement around the eye.
3. Occasional loss during sleep or
while rubbing eyes.
4. Interference with vision.
5. Difficulty in placement & removal.
Types Of Ocular Control Release System
A) Non-Erodible :
1.Ocusert:
Developed by Alza Corporation,
Oval flexible ocular insert,
Release Rate:20-40mg/hr
for 7day
Consist of-

Annular ring : Impregnated with Ti0
2
: For Visibility

Part Material
Drug Reservoir Pilocarpine
Carrier material Alginic acid
Rate controller Ethylene vinyl acetate copolymer
Energy Source Conc. Of Pilocarpine
Delivery Portal Copolymer membrane
2) Contact Lens :
Presoaked Hydrophilic lens.
Drug Release : within 1
st
30 Min.
Alternate approach : incorporate drug
either as sol
n
or suspension of solid monomer mixture.
Release rate is up to : 180 hr.

3) Diffusional Inserts :
Central reservoir of drug enclosed in Semi permeable or micro
porous membrane for diffusion of drug.
Diffusion is controlled by Lacrimal Fluid penetrating through it.
It prevents continues decrease in release rate due to barrier.
Release follows : Zero Order Kinetics.

B) Erodible Inserts

1.Lacrisert:
Sterile, Rod Shaped device.
Composition: HPC without preservative.
Weight:5mg,
Dimension:Diameter:12.5mm, Length:3.5mm
Use:-Dry eye treatment, Keratitis Sica.

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Lacrisert
Each LACRISERT is 5 mg of hydroxypropyl cellulose. LACRISERT contains
no preservatives or other ingredients. It is about 1.27 mm in diameter by
about 3.5 mm long.
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How to apply LACRISERT in eye

2.SODI: Soluble Ocular Drug Insert.
Small water soluble developed for Cosmonauts who could not use
their eye drop in liquid condition.
Composition : Acryl amide, Vinyl Pyrolidone, Ethylacrylate.
Weight 15-16 mg.
In 10-15 sec Softens;
In 10-15 min. turns in Viscous Liquids;
After 30-60min. Becomes Polymeric Solution.

Advantages of SODI
Single SODI application :replaces 4-12 eye drops Instillation,or 3-6
application of Ointments.
Once a day treatment of Glaucoma & Trachoma.

3)Minidisc:
It is made up of counter disc with Convex front &
Concave back surface in contact with eye ball.
4-5mm in diameter.
Composition : Silicon based pre polymer.
Hydrophilic or Hydrophobic.
Drug release from 170 hr.

C) Nanoparticle:
For water soluble drugs.
Size:10-1000nm
Drug is Dispersed, Encapsulated, or Absorbed
Produced by Emulsion Polymerization
Chemical initiation, Gamma irradiation, Visible light.
Polymerization is carried out by :
Emulsifier stabilizes polymer particle
Polymer used are Biodegradable.
E.g. :- Nanoparticle of Pilocarpine enhances
Mitotic response by 20-23%.
D) Liposome
Biodegradable, Non-toxic in nature.
Vesicle composed of lipid membrane enclosed in an
aqueous volume.
Formed when matrix of phospholipids is agitated in
aqueous medium to disperse two phase.
Phospholipids used are : Phophotidylcholine, Phophotidic
acid,
Sphingomyline,
Phosphotidyleserine,
Cardiolipine
.
Advances in ocular drug delivery
1. Ophthalmic gel for pilocarpine
Poloxamer 407 (low viscosity, optical clarity, mucomimetic
property)
2. Ophthalmic prodrug
Dipivalyl epinephrine (Dipivefrin)
Lipophilic increase in corneal absorption
Esterase within cornea and aqueous humor
3. Continuous delivery system based upon the osmotic
property
Thin flat layer, contoured three-dimensional unit
Conform to the space of the upper cul-de-sac
Delivery of diethyl carbamazine in ocular onchocerciasis

4.Gel delivery system
Biodegradable polyisobutyl-cyano acrylate (PIBCA) colloidal
particulate system of pilocarpine to incorporate it into a
Pluronic F127 (PF 127)-based gel delivery system.
5)Mucoadhesive Polymer.
mucoadhesive polymer, the tamarind seed polysaccharide, as
a delivery system for the ocular administration of hydrophilic
and hydrophobic antibiotics.
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Polymers used in ocular drug delivery
Acacia gum
Alginic acid
Carbomers
Hydroxypropyl methylcellulose (HPMC)
Sodium hyaluronate
Pectin
Polyvinyl alcohol (PVA)
Polyvinylpyrrolidone (PVP)
Tragacanth
Dextran
Gelatin
Poly acrylic acid

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PHYSICO-CHEMICAL
EVALUATIONS OF OCUSERTS

Physical appearance and surface texture:
Includes visual inspection and texture evaluation by
feel or touch. Done for both films and ocuserts.

Surface pH:
Surface pH of the inserts was determined by
allowing them to swell in a closed Petri dish at room
temperature for 30 min in 0.1 ml of distilled water. The
swollen devices were removed and placed on pH paper
to determine the surface pH. After 1 min the colour
developed was compared with the standard colour scale.
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Thickness:
If thickness varies from one film to another, the drug
release from the film also varies. So it is must to keep
the thickness of the film uniform to get reproducible
results. In the present study, the thickness of the
formulated films as well as ocular inserts was measured
using tablet tester (least count 0.002 mm). Average of
10 films/inserts and standard deviation values were
calculated.
Weight Variation:
As weight variation between the formulated films can
lead to difference in drug content and in vitro behaviour,
evaluation was carried out by weighing 10 films/ocuserts
by an electronic balance (least count 0.1 mg). The
average weight and standard deviation were then
calculated and reported.

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Moisture Uptake:
The percentage moisture uptake test was carried out
to check the physical stability or integrity of the film.
Ocular inserts were weighed and placed in a dessicator
containing 100 ml of saturated solution of sodium
chloride (~ 75 % humidity). After three days, films were
taken out and reweighed; the percentage moisture
uptake was calculated by using following formula.
Final weight Initial Weight
Percentage moisture uptake = --------------------------- ------------- x100

Initial weight
Moisture Loss:
The percentage moisture loss test was carried out to
check the integrity of the film at dry condition. Ocular
films were weighed and placed in a dessicator containing
anhydrous Calcium chloride. After three days, films were
taken out and reweighed; the percentage moisture loss
was calculated by using following formula.

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Initial weight Final Weight
Percentage moisture loss = ---------------------- 100
Initial weight
Folding Endurance:
The flexibility of polymeric films can be measured
quantitatively in terms of folding endurance.
Folding endurance was determined by
repeatedly folding a small strip of ocular film
(approximately 22 cm) at the same place till it
broke. The number of times film could be folded
at the same place, without breaking gives the
value of folding endurance.

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Determination of Drug Content:
Drug content was estimated by placing an ocular
insert in 20 ml of phosphate buffer pH 6.8 with
stirring in shaking incubator for about 24 hr at 37
0C. The solution is filtered and one ml of the
solution was withdrawn, diluted and measured
by UV-visible spectrophotometer . Similarly, a
blank solution was prepared using dummy film.
Average drug content of three films was
determined.
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In vitro Release Study
The in vitro drug release from different ophthalmic inserts was
studied by using the classical standard cylindrical tube which has
the diameter 15 mm. Dialysis membrane, which acted as corneal
epithelium, was tied to one end of open cylinder which acted as
donor compartment.
An ocular insert was placed inside this compartment with 0.7 ml of
simulated tear fluid (STF). The entire surface of the membrane was
in contact with the receptor compartment containing 200 ml of STF
(pH 7.4).
The content of the receptor compartment was stirred continuously
at 25 rpm. Samples of 1 ml were withdrawn from the receptor
compartment at periodic intervals and replaced by equal volume of
fresh buffer solution.
The samples were analyzed spectrophotometrically against
reference standard using STF as blank.
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Drug-Excipient Interaction Studies:
Interaction studies were conducted on the
optimized formulation by comparing it with the
pure drug and the placebo formulation (without
drug) on the basis of the assay, UV and IR
spectroscopy.
The optimized inserts were powered in the
mortar and extracted with 20 ml of distilled
water. The extract was transferred to the
volumetric flask of 50 ml capacity and made to
the volume. It was then filtered through
Whatman filter paper No. 42. The absorbance of
the filtered solution was determined
spectrophotometrically at 290 nm.
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IN VITRO ANTIBACTERIAL
ACTIVITY
The optimized ocular insert was evaluated
microbiologically for controlled drug release for 24 hours.
The test microorganisms were E. coli and S. aureus.
A layer of Agar (10 ml) was allowed to solidify in the Petri
dish. An ocusert was removed from the pack and carefully
placed over the agar layer and a second layer of Agar (10
ml) was applied to cover the insert.
After solidification, the Petri dish was incubated in inverted
position for 24 hours at 370.5
o
C. After incubation, the
length, width and area of zone of inhibition were measured
around the ocular insert and it was compared with that of
eye drops.
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STERILITY TESTING (I.P. 1996 )

The tests for sterility are intended for detecting the
presence of viable forms of microorganisms in
ophthalmic preparations.
The principle governing these tests is that if the
microorganisms are placed in a medium which provides
nutritive material and water, kept at a favourable
temperature, the organisms will grow and their presence
can be indicated by turbidity in the originally clear
medium.
In the present study, two media namely, alternative
thioglycolate medium (ATGM) and soyabean-casein
digest medium (SBCD) were used to investigate the
presence/absence of aerobic, anaerobic bacteria and
fungi, in the UV sterilized ocular inserts.
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IN VIVO STUDIES
Approval for the use of animals in the
study was obtained from the Institutional
Animal Ethics Committee (IAEC). Rabbits
of either sex weighing 2.1 to 2.7 kg were
used for in vivo studies. The rabbits were
housed singly in restraining cages during
the experiment and allowed food and
water. Free lag and eye movement was
allowed
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In Vivo Release Study
On the day of experiment the sterilized ocuserts were
placed into the lower conjunctival cul-de-sac of rabbits.
The inserts were inserted into one eye of seven rabbits
at same time and another eye served as control. After 1,
2, 4, 6, 10, 22 and 24 hrs, the inserts were carefully
removed and analyzed for remaining drug content by
HPLC analysis. The amount of drug remaining,
calculated from the area of the HPLC spectra obtained,
was subtracted from initial drug content of inserts to find
the amount of drug released in the rabbit eye.
Observations for any fall out of insert were also recorded
throughout the experiment
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In vivo Anti-Bacterial Activity Evaluation
Two rabbits were selected and examined for the
absence of any ophthalmic disease. Equal
volume (0.1 ml) of well distributed suspension of
Staphylococcus aureus was instilled in to the
right eye of both the rabbits.
Conjunctival swabs were collected from the
right eye of either rabbits at the predetermined
time intervals and cultured in nutrient agar
medium by streak plate method.

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In vivo Anti-Bacterial Activity Evaluation
The growth was noted after incubation for 24 hrs. Soon
after the conjunctival swabs were collected at 0th hour,
one ocusert was inserted into the cul-de-sac of right eye of
rabbit 1 and two drops of eye drop were instilled into the
cul-de-sac of rabbit 2, while the left eye of the either
rabbits was used as a control.
Conjunctival swabs were collected and cultured at an
interval of 6 hours for 24 hours. The eye drops were
added after the collection of the swabs at the same time
interval.
All five cultures collected in the time interval of 6 hrs, every
culture was examined for growth of bacteria after 24 hours
of its incubation.

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AGEING STUDY:
The optimized inserts were stored in amber
colored glass bottles at 3 different temperatures
4
o
C, Room temperature and 37
o
C for a period
of 2 months. The samples were withdrawn after
30, 45 and 60 days and analyzed for physical
appearance, drug content and sterility.
Reference:
N.K.Jain, Advances in Controlled & Novel Drug Delivery,
CBS Publication, & distributor, New Delhi, pg No.219-223.
Remington & Gennaro ; The Science & Practice Of
Pharmacy. Mack Publication Company. Easton, Pennsylvania.
Pg. No. 1563-1567.
Web Sites:
www.vision-care-guide.com
www.google/images/eye/anatomy& physiology

Creativity is allowing one self to make mistakes.
Art is knowing which one to keep.

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