Occular drug delivery system

Presented by, Facilitated by,

Pratiksha C Chandragirivar Dr. Anita Desai
M pharma 1st sem HOD and professor
Dept. of pharmaceutics Dept. of pharmaceutics
HSK COP Bagalkot HSK COP Bagalkot

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CONTENTS:

1. Introduction
2. The eye
3. Barriers of drug permeation
4. Methods to overcome barriers

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INTRODUCTON:

Definition:
Occular drug delivery system: These are the special
dosage forms designed to be instilled onto the external surface
of the eye (topical),administered inside(intraocular)or
adjacent(periocular) to the eye or used in conjuction with the
devices.

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 The eye is a unique organ, both anatomically, and
physiologically, containing several widely varied structures
with independent physiological functions.
 The complexity of the eye provides unique challenges to drug
delivery strategies.
 Ocular drug delivery is one of the most challenging tasks faced
by the Pharmaceutical researchers.
 One of the major barriers of ocular medication is to obtain and
maintain a therapeutic level at the site of action for prolonged
period of time.

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 Pharmaceutical treatment and drug delivery methods for
treating eye diseases and disorders vary considerably
depending on the nature and extent of the disease or disorder
 The bioavailability of ophthalmic drugs is, however, very poor
due to efficient protective mechanisms of the eye.

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 lachrymation, effective drainage by the nasolacrimal system,
the inner and outer blood-retinal barrier, the impermeability of
the cornea, and inability of absorption by other non-corneal
structures cause the eye to be exceedingly impervious to
foreign substances.

LACRIMAL APPARATUS SHOWN IN AN ANTERIOR VIEW OF THE RIGHT EYE

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 While these innate barriers are advantageous for hindering
the invasion of undesired molecules, pathogens, and
particulates, they pose significant challenges to delivering
ocular drugs.
 Three important factors have to be considered when
attempting drug delivery to the eye-
1. How the blood-eye barrier (systemic to ocular) or cornea
(external to ocular) is crossed by the drug to reach the site of
action
2. How to localize the pharmacodynamic action at the eye and
minimize drug action on other tissues.
3. How to prolong the duration of drug action such that the
frequency of drug administration can be reduced.

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THE EYE:

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 The eyelids contain skeletal muscle that enables the eyelids to
close and cover the front of the eyeball.
 Eyelashes along the border of each eyelid help keep dust out of
the eyes.
 The eyelids are lined with a thin membrane called the
conjunctiva, which is also folded over the white of the eye and
merges with the corneal epithelium. Inflammation of this
membrane, called conjunctivitis, may be caused by allergies or
by certain bacteria or viruses, and makes the eyes red, itchy,
and watery.
 Tears are produced by the lachrymal glands, located at the
upper, outer corner of the eyeball, within the orbit.

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 Secretion of tears occurs constantly, but is increased by the
presence of irritating chemicals or dust, and in certain
emotional situations.
 Small ducts take tears to the anterior of the eyeball, and
blinking spreads the tears and washes the surface of the eye.
 Tears are mostly water, with about 1% sodium chloride,
similar to other body fluids.
 Tears also contain lysozyme, an enzyme that inhibits the
growth of most bacteria on the wet, warm surface of the eye.

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 The medial corner of the eyelids are two small openings into
the superior and inferior lachrymal canals.
 These ducts take tears to the lachrymal sac (in the lachrymal
bone), which leads to the nasolachrymal duct, which empties
tears into the nasal cavity. This is why crying often makes the
nose run.

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BARRIERS TO DRUG PERMEATION:

 The human eye has a spherical shape with a diameter of

23mm.
 The structural components of the eyeball are divided into three
layers:
a. The outermost coat comprises the clear, transparent cornea
and the white, opaque sclera
b. The middle layer comprises the iris anteriorly, the choroid
posteriorly, and the ciliary body
c. The inner layer is the retina, which is an extension of the
central nervous system.

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Mainly it is classified into two major categories:-

A. Physiological Barriers

B. Anatomical Barriers

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A. Physiological Barriers :

 The eye’s primary line of defense is its tear film.

 Bioavailability of topically administered drugs is further
reduced by precorneal factors, such as solution drainage, tear
dilution, tear turnover, & increased lacrimation.
 The lacrimal fluid is an isotonic aqueous solution containing a
mixture of proteins, such as lysozyme & lipids.
 Following topical application, lacrimation is significantly
increased leading to dilution of administered dose.
 Lowering of drug concentration is seen leading to diminished
drug absorption.

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 Rapid clearance from the precorneal area by lacrimation &
through nasolacrimal drainage & spillage further reduces
contact time between the tissue & drug molecules.
 This in-turn lowers the exact time for absorption leading to
reduced bioavailability.

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B. Anatomical Barriers:

 When a dosage form is topically administered there are two

routes of entry, either through the cornea or via the non-
corneal route.
 Epithelium is a very tight multilayered tissue that is mainly
composed of 5 sections.
 Epithelium acts as the principal barrier.
 It acts as a major barrier to hydrophilic drug transport through
intercellular spaces.
 Non- corneal route bypasses the cornea & involves movement
across conjunctiva & sclera.

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 This route is important especially for large & hydrophilic
molecules such as peptides, proteins & siRNA.
 The conjunctiva is more permeable than cornea especially for
hydrophilic molecules due to much lower expression of tight
junction proteins relative to corneal epithelium.

Anatomical barriers are further classified as :-

1. Ocular surface Barriers

2. Ocular wall Barriers
3. Retinal Barriers

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1. Ocular surface Barriers

 The corneal and conjunctival superficial layers form the ocular

surface that is in contact with the tear film.
 The ocular surface is to create a defense barrier against
penetration from undesired molecules.
 The corneal surface is only 5% of the total ocular surface and
the remaining 95% is occupied by the conjunctiva.
 The cornea is made up of five layers :
(a) epithelium (b) Bowman’s layer
(c) stroma (d) Descemet’s membrane
(e) endothelium.

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 The outermost layers of the corneal squamous epithelial cells
form a barrier for intercellular drug penetration.

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2. Ocular wall Barriers

 The skeleton of the eye globe consists of the rigid scleral

collagenous shell that is lined internally by the uveal tract.
 The scleral stroma is composed of bundles of collagen,
fibroblasts, & a moderate amount of ground substance.
 This stroma which consists of multiple layers of hexagonally
arranged collagen fibers containing aqueous pores or
channels allow hydrophilic drugs to easily pass through but it
acts as a significant barrier for lipophilic drugs.
 The eye also contains the choroid which is a very highly
vascularized tissue, with One of the highest blood flow rates
among body tissues.

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3. Retinal Barriers:

 The retina consists of 10 layers :

(a) The retinal pigment epithelium,
(b) Photoreceptor outer segments
(c) external limiting membrane,
(d) outer nuclear Layer,
(e) outer plexiform layer,
(f) inner nuclear layer,
(g) inner plexiform layer,
(h) Ganglion cell layer,
(i) nerve fiber layer,
(j) internal limiting membrane.

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METHODS TO OVERCOME BARRIERS:

It involves two approaches:

• Bioavailability improvement
• Control drug delivery system

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• Bioavailability improvement

1. Viscosity enhancer
2. Eye ointment
3. Gel
4. Prodrug
5. Penetration enhancer
6. Liposomes
7. Niosomes
8. Nanoparticles
9. Nano suspension
10. Micro emulsion
11. In situ forming gels

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1.Viscosity enhancer:

• Viscosity increasing polymers are usually added to opthalmic

drug solutions which leads to increased in vehicle viscosity.
• That helps in slower elimination from the preocular area,
which lead to improve precorneal residence time.
• Hence a greater trans corneal penetration of the drug into the
anterior chamber
Ex: PVA, PVP, Methyl cellulose, HPMC, HPC

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2.Eye ointment:

• Ointments are usually formulated using mixtures of semisolid

and solid hydrocarbons (paraffin).
• It should have melting or softening point close to body
temperature and should be non irritating to the eye
• Ointments may be of simple bases, or compound bases where
a two phased system is employed.
• Upon instillation in the eye, the ointments break up into small
droplets and remain as a depot of drug in the cul-de-sac for
extended periods.

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• Hence useful in improvising drug bioavailability and
sustaining drug release
• It’s safe and well tolerated by the eye but having poor patient
compliance due to blurring of vision and occasional irritation.

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3.Gel :

• Ophthalmic gels are composed of mucoadhesive polymers that

provide localized delivery of an active ingredient to the eye.
• Such polymer have a property known as bioadhesion meaning
attachment of a drug carrier to a specific biological tissue.
E.x: PVP, HPMC, HPC

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4. Prodrug :

• The principle of prodrug is to enhance corneal drug

permeability through modification of the hydrophilicity ( or
lipophilicity) of the drug.
• Within the cornea or after corneal penetration the prodrug is
chemically or enzymatically metabolized into the active parent
compound.
• The ideal prodrug should not only have increased lipophilicity
and a high partition coefficient, but it must also have high
enzyme susceptibility.
• Enzymes in ocular tissues include esterase’s, ketone reductase,
and steroid 6- hydroxylase.
Ex. Acyclovir, Ganiclovir

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5. Penetration enhancer:

• The transport characteristics across the cornea can be

maximized by increasing the permeability of the corneal
epithelial membrane.
• The stratified corneal epithelial cell layer is a ‘tight’ ion
transporting tissue having high resistance of 12-16 kΏcm2
being exhibited by the paracellular pathway.
• So, one of the approaches used to improve ophthalmic drug
availability by improvising permeability characteristics of
occular using penetration enhancers.

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• It has main disadvantage of ocular irritation and toxicity
• permeation enhancers increase corneal uptake by modifying
the integrity of the corneal epithelium.
• Permeation enhancing agents such as cetylpyridinium chloride,
ionophore such as benzalkonium chloride, Parabens, tween 20,
saponins, etc

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6.Liposomes:

• Liposomes are the microscopic vesicles composed of one or

more concentric lipid bilayers, separated by water or aqueous
buffer compartments.
• Liposomes possess the ability to have an intimate contact with
the corneal and conjunctival surfaces, which increases the
probability of ocular drug absorption.
• Liposomes works on the principles of surface charge where
positively charged liposomes seem to be preferentially
captured at the negatively charged corneal surface.
• It is bio degradable, biocompatible in nature and toxicity of the
drug is reduced
• It provides the sustained release and site specific delivery.
• It has limitation like inadequate aqueous stability.

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7.Niosomes:

• Niosomes are bilayered structural vesicles made up of non-

ionic surfactant which are capable of encapsulating both
lipophilic and hydrophilic compounds.
• Niosome reduce the systemic drainage and improve the
residence time, which leads to increase ocular bioavailability.
• The drug releases independent of pH, resulting in significant
enhancement of ocular bioavailability.

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8.Nano particles:

• These are polymeric collodial particles, ranging from 10nm-

1mm, in which the drug leads to stabilization of the drug.
• Encapsulation of the drug leads to stabilization of the drug.
• They represent promising drug carriers for ophthalmic
application
• Its bioadhesive properties, resulting in an increase in the
residence time and biological response, hence it improves the
ocular bioavailability of the drug and reduced dosing
frequency.
• Nanoparticles of poly-e-caprolactone containing cyclosporine
show a better corneal absorption.

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9. Nano suspension:

• 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.
• Nano suspensions contains polymeric results which are inherit
in nature.
• Charge on the surface of nanoparticles facilities its adhesion to
the cornea, and thus improves bioavailability by prolonging
the contact time.
• Cloricomen (AD6) was formulated in nano suspension by
using eudragit.

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10. Micro emulsion:

• Micro emulsion is stable dispersion of water and oil, facilitated

by a combination of surfactant and co-surfactant in a manner
to reduce interfacial tension.
• Micro emulsion improves the ocular bioavailability of the drug
and reduces frequency of the administration by higher
thermodynamic stability, small droplet size (~100nm), and
clear appearance
• An example oil in water system consisting of pilocarpine using
lecithin, PG, PEG 200 as surfactant/co surfactants, and
isopropyl Myristate as the oil phase.

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11. In situ-forming gel:

• The droppable gels are liquid upon instillation, and they

undergo a phase transition in the ocular cul-de-sac to form a
viscoelastic gel, and this provides a response to the
environmental changes.
• It prolongs the residence time and improves the ocular
bioavailability of the drug.
• Parameters that can change and trigger the phase transaction of
droppable gels include PH, change CAP latex, cross linked
polyacrylic acid.

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• Control drug delivery system:

It involves :
1. Microparticles
2. Ocular insert
3. Implants

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1. Microparticle:

• Micro particles are drug containing, micron- sized polymeric

particles suspended in a liquid medium
• Drugs can be physically dispersed in the polymer matrix or
covalently bound to the polymer backbone
• The particles reside in the ocular cul-de-sac, and the drug is
released from particles through diffusion, chemical reaction
and polymer degradation.
• It improves precorneal residence time, which leads to
continuous and sustain release of the drugs, followed by
improved ocular bioavailability of the drug and reduced dosing
frequency.

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2. Ocular insert:

• The ocular inserts provide more controlled, sustained and

continuous drug delivery by maintaining an effective drug
concentration in the target tissues and minimizing the number
of applications.
• It provides accurate dosing of the drug
• A number of ocular inserts were prepared utilizing different
techniques to make soluble, erodible, non erodible, and
hydrogel inserts.

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3.Implants :

• The intraocular implant design is to provide prolonged activity

with controlled drug release from the polymeric implant
material.
• The implants requires minor surgery where they are placed
intravitreally at the pars plana of the eye (posterior to the lens
and anterior to the retina)
• Implants are classified into non biodegradable and
biodegradable.
• Non biodegradable provides accurate control of drug release
and longer release periods but require surgical implant
removal which is risky.

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REFERENCES
1. Lang JC Recent developments in ophthalmic drug delivery:
conventional ocular formulations.
2. Control and novel drug delivery system by N.K JAIN -
edition 2011.
3. https://www.pharmatutor.org/articles/review-on-ocular-drug-
delivery?page=1
4. https://www.wjgnet.com/2220-3192/full/v2/i4/78.htm
5. http://ijpsr.com/bft-article/ocular-drug-delivery-a-
review/?view=fulltext
6. https://www.researchgate.net/publication/235924442_OCUL
AR_DRUG_DELIVERY_A_REVIEW/link/0fcfd5143952a8
8021000000/download

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 Thank you

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