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INTRODUCTION
Ocular administration of drug is
primarily associated with the need totreat ophthalmic diseases.
Eye is the most easily accessible site fortopical administration of a medication.
Ideal ophthalmic drug delivery mustbe able to sustain the drug release and
to remain in the vicinity of front of theeye for prolong period of time.
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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%.
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EYE AND LACRIMAL DRAINAGE
SYSTEM
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ANATOMY OF EYE:
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ROUTES OF DRUG DELIVERY IN EYE
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MECHANISM OF OCULAR
ABSORPTIONNon- corneal absorption:
Penetration across sclera & conjunctiva into intra
ocular tissues.
Non productive: because penetrated drug isabsorbed by general circulation.
Corneal absorption:
Outer epithelium: rate limiting barrier, with pore
size 60a, only access to small ionic and lipophilicmolecules.
Trans cellular transport: transport between
corneal epithelium and stroma.
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FACTORS AFFECTING
INTRAOCULAR BIOAVAILABILITY:
1. Inflow & outflow of lacrimal fluids.
2. Efficient naso-lacrimal drainage.
3. Interaction of drug with proteins oflacrimal fluid.
4. dilution with tears.
5. Corneal barriers.
6. Active ion transport at cornea.
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BARRIERS AVOIDING DRUG DELIVERY
Drug in tear fluid
Ocular absorption
Corneal route Conjunctival and scleral route Systemic absorption50-100% of dose
Major route- conjunctiva of eye, nose
Minor route- lacrimal drainage system,
pharynx, GIT, aqueous humor
Aqueous humor
Ocular tissue ELIMINATION
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OPHTHALMIC DOSAGE FORM
Ophthalmic preparations are sterileproducts essentially free from foreignparticles, suitably compounded andpackaged for instillation in to the eye.
The following dosage forms have beendeveloped to ophthalmic drugs.
Some are in common use, some are
merely experimental, and others are nolonger used.
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OCULAR DELIVERYSYSTEMS
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
DISCOMESPHARMACOSOMES
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SELECTED TYPES OF
OCDDS:
1. Aqueous eye drops2. Oily eye drops
3. Eye ointments
4. Eye lotions
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5. Paper strips
6. Ocuserts
7. Hydro gel contact lenses
8. Collagen shields
9. Ophthalmic rods
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ADVANTAGES:
They are easily administered by the nurseThey are easily administered by the
patient himself.
They have the quick absorption andeffect.
less visual and systemic side effects.
increased shelf life.better patient compliance.
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DISADVANTAGES:
The very short time the solutionstays at the eye surface.
Its poor bioavailability.
The instability of the dissolved
drug.
The necessity of using preservative.
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IDEAL CHARACTERISTICS OF
OCDDS:Sterility
Isotonicity-e.g.:
1.9% boric acid, 0.9% NaCl
Buffer/pH adjustment
Less drainage tendency
Minimum protein binding
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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
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Ointment and Gels:
Prolongation of drug contact timewith the external ocular surface can
be achieved using ophthalmic
ointment vehicle but, the majordrawback of this dosage form like,
blurring of vision & matting of eyelids
can limit its use.
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Ocuserts and Lacrisert:
Ocular insert (Ocusert) are sterile preparation that
prolong residence time of drug with a controlled releasemanner and negligible or less affected by nasolacrimaldamage.
Inserts are available in different varieties depending
upon their composition and applications.Lacrisert is a sterile rod shaped device for thetreatment of dry eye syndrome and keratitis sicca.
They act by imbibing water from the cornea and
conjunctiva and form a hydrophilic film which lubricatesthe cornea.
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2) VESICULAR SYSTEM:
Liposomes:
Liposomes are biocompatible and
biodegradable lipid vesicles made
up of natural lipids and about2510 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 partitioncoefficient, poor solubility or those with medium to high
molecular weights and thus increases the probability of
ocular drug absorption.
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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 ofnon-ionic surface active agents rather than phospholipidsas 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
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6. Microneedle:Microneedle had shown prominent in vitro penetration
into sclera and rapid dissolution of coating solution afterinsertion while in vivo drug level was found to be
significantly higher than the level observed following topicaldrug 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 forestablishing electrostatic interactions
A mucoadhesive drug formulation for the treatment ofglaucoma was developed using a highly potent beta blockerdrug, levobetaxolol(LB) hydrochloride and partiallyneutralized poly acrylic acid(PAA).
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INSERTS
CLASSIFICATION :
1 .NON ERODIBLE INSERTS
i. Ocusert
ii. Contact lens
2 .ERODIBLE INSERTS
i. Lacriserts
ii. SODI
iii. Mindisc
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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
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ADVANTAGES:
Reduced local side effects andtoxicity.
Around the clock control of IOP.
Improved compliance.
DISADVANTAGES:
Retention in the eye for the full 7days.
Periodical check of unit.Replacement of contaminated unit
Expensive.
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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
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2) ERODIBLE INSERTS:
The solid inserts absorb the aqueous tear fluid
and gradually erode or disintegrate. The drug isslowly 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
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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 shapeWeighs 15-16 mg
Use glaucoma
Advantage Single application
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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
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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.
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PERCENTAGE MOISTURE ABSORPTION:
Here ocular films are weighed and placed in
a dessicator containing 100 ml of saturatedsolution of aluminium chloride and 79.5%
humidity was maintained.
After three days the ocular films arereweighed and the percentage moisture
absorbed is calculated using the formula =
% moisture absorbed = Final weight initial weight/ initial weight x 100
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INVITRO EVALUATION METHODS:
BOTTLE METHOD:
In this, dosage forms are placed in the bottlecontaining dissolution medium maintained at specified
temperature and pH.
The bottle is then shaken.
A sample of medium is taken out at appropriateintervals and analyzed for the drug content.
DIFFUSION METHOD:
Drug solution is placed in the donor compartment andbuffer medium is placed in between donor and receptor
compartment.
Drug diffused in receptor compartment is measured at
various time intervals.
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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 isrotated 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.
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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 atregular time interval and are analyzed for drug
content.
The drug remaining is subtracted from theinitial drug content, which will give the amountof the drug absorbed in the eye of animal atparticular time.
After one week of washed period, theexperiment was repeated for two time as before.
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ACCELERATED STABILITY STUDIES:
These are carried out to predict thebreakdown that may occur over prolongedperiods 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 sampleis taken and analyzed for drug content.
From these results, graphical datatreatment is plotted and shelf life and expirydate are determined.
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CONCLUSION:
All approaches improve ocular drugbioavailability by increasing ocular drug
residence time, diminish side effects due to
systemic absorption and diminishing thenecessary 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.
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