Ocular Drug Delivery System (ODDS) Description of human eye Fluid system of eye Barriers of Drug permeation Methods to overcome barriers

1. Ocular Drug Delivery System
Simran
M.Pharmcy Ist year
GURU GOBIND SINGH COLLEGE OF PHARMACY
YAMUNANAGAR

2. Contents
 Introduction
 Human eye
 Barriers of drug permeation
 Methods to overcome barriers

3. Introduction
 Ocular drug delivery has been a major challenge to pharmacologists and drug delivery scientists
due to its unique anatomy and physiology. Static barriers (different layers of cornea, sclera, and
retina including blood aqueous and blood–retinal barriers) , dynamic barriers (choroidal and
conjunctival blood flow, lymphatic clearance, and tear dilution).
 The anatomy, physiology, and biochemistry of the eye render this organ highly impervious to
foreign substances.
 A significant challenge to the formulator is to circumvent the protective barriers of the eye without
causing permanent tissue damage. These barriers affect the bioavailability of drugs.
 In ocular drug delivery system, there is a main problem of rapid and extensive elimination of
conventional eye drops from eye. This problem results in extensive loss of drug. Only a few
amount of drug penetrates the corneal layer and reached to internal tissue of eye. The main region
of drug loss includes lachrymal drainage and drug dilution by tears.
 This indulgence reduces the ocular bioavailability and lead to undesirable side effect and toxicity.

4. Human eye
 Diameter 23 mm
 Structure comprises of three layers
1. Outermost coat: The clear, transparent cornea and the white, opaque Sclera
2. Middle layer: The iris anteriorly, the choroid posteriorly, and the ciliary body at the intermediate part
3. Inner layer: Retina (extension of CNS)
 Cornea
 Epithelium
 stroma
 endothelium (fat-water-fat structure)
 Function: Penetration of the drug depends On Oil-water partition coefficient.

6. Fluid systems in eye
1.Aqueous humor
• Secreted from blood through epithelium of the ciliary body.
• Secreted in posterior chamber and transported to anterior chamber.
2.Vitreous humor
• Secreted from blood through epithelium of the ciliary body.
• Diffuse through the vitreous body.
Lacrimal glands
• Secrete tears & wash foreign bodies.
• Moistens the cornea from drying out.

7.  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.
 The cornea: The front portion of the sclera, is transparent and allows light to enter the
eye. The cornea is a powerful refracting surface, providing much of the eye’s focusing
power.
 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.
 The Iris : is the part of the eye that gives it color. It consists of muscular tissue that
responds to surrounding light, making the pupil, or circular opening in the center of the
iris, larger or smaller depending on the brightness of the light.

8.  The lens is a transparent, biconvex structure, encased in a thin transparent covering. The
function of the lens is to refract and focus incoming light onto the retina.
 The retina is the innermost layer in the eye. It converts images into electrical impulses that
are sent along the optic nerve to the brain where the images are interpreted.
 The macula is located in the back of the eye, in the center of the retina. This area produces
the sharpest vision.

9. Barriers of Drug permeation
These barriers can be classified as
1.Anatomical barriers
2.Physiological barriers
3.Blood ocular barriers

10. Barriers of Drug permeation

12. 1.Anatomical Barrier: When a dosage form is topically administered there are two routes of
entry, either through the cornea or via the non-corneal route.
The cornea is composed of five sections:
 Epithelium
 bowman’s membrane
 Stroma
 Descemet’s membrane
 endothelium
Epithelium acts as the principal barrier. It acts as a major barrier to hydrophilic drug transport
through intercellular spaces.
Stroma consists of multiple layers of hexagonally arranged collagen fibers containing aqueous
pores allow hydrophilic drugs to easily pass through but it acts as a barrier for lipophilic drugs.
Non-corneal route bypasses the cornea and involves movement across conjunctiva and sclera.

13. Anatomical barriers are further classified as
1. Ocular surface Barriers
2. Ocular wall Barriers
3. Retinal Barriers
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.

14.  The cornea is made up of five layers:
(a) epithelium
(b) Bowman’s layer
(c) stroma
(d) Descemet’s membrane
(e) endothelium.

15. 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.

16. 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.

17.  Blood-Retinal Barrier - Blood-retinal barrier (BRB) restricts drug transport from blood
into the retina. BRB is composed of tight junctions of retinal capillary endothelial cells and
RPE, called iBRB for the inner and BRB for the outer BRB, respectively. The retinal
capillary endothelial cells are not fenestrated and have a paucity of vesicles.
 Blood-ocular barriers: The eye is protected from the xenobiotics in the blood stream by
blood-ocular barriers. These barriers have two parts: blood-aqueous barrier and blood-
retina barrier. The anterior blood-eye barrier is composed of the endothelial cells in the
uveam.
 This barrier prevents the access of plasma albumin into the aqueous humor, and also limits
the access of hydrophilic drugs from plasma into the aqueous humor.

18. 2. Physiological Barriers :
 Bioavailability of topically administered drugs is further reduced by precorneal factors,
such as solution drainage, tear dilution, tear turnover, & increased lacrimation.
 Following topical application, lacrimation is significantly increased leading to dilution
of administered dose.
 Lowering of drug concentration is seen leading to diminished drug absorption.
 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.
 Reflex blinking
 Tear dilution
 Metabolism
 Nasolacrimal drainage of drug solution

19. Other Barriers
 Drug loss from the ocular surface: After instillation, the flow of lacrimal fluid removes
instilled compounds from the surface of eye. Even though the lacrimal turnover rate is only
about 1 µl/min the excess volume of the instilled fluid is flown to the nasolacrimal duct
rapidly in a couple of minutes.
• Another source of non-productive drug removal is its systemic absorption instead of ocular
absorption.
• Systemic absorption may take place either directly from the conjunctival sac via local blood
capillaries or after the solution flow to the nasal cavity.
 Lacrimal fluid-eye barriers: Corneal epithelium limits drug absorption from the lacrimal
fluid into the eye. The corneal epithelial cells form tight junctions that limit the paracellular
drug permeation.
• Therefore, lipophilic drugs have typically at least an order of magnitude higher
permeability in the cornea than the hydrophilic drugs.

20. Methods to overcome barriers
A.DRUG DELIVERY BY NOVEL ROUTES
Scientists have experimented with alternate routes of drug delivery that can overcome barriers
presented by the more conventional routes. Injections through visible portions of the sclera targeting
various sections of ocular structures are routinely carried out by a trained specialist.
1.Intravitreal injection
Intravitreal injection (IVI) involves delivering of the drug formulation directly into the vitreous humor
through pars plana. This method provides direct access to the vitreous and avoids both the cornea and
also the scleral blood vessels. Formulations such as solution, suspension or a depot formulation can be
administered through this route.

21. 2.Subconjunctival injections
This injection delivers the drug beneath the conjunctival membrane that lines the inner surface of
eyelid. It allows for circumvention of both cornea and conjunctiva allowing the drug direct access
to the sclera. It is much less invasive with lesser side effects when compared to intravitreal
injections. The method is an excellent route for delivering hydrophilic drugs as it bypasses their
rate-limiting barriers allowing more drugs to enter into the vitreous.
3. Sub-tenon injections
Sub-tenon injections are administered into a cavity between tenon’s capsule and sclera using a
blunt cannula. Pre-operative deep sedation is also not a requirement for this procedure. Sub-tenon
route appears to be a better and safer route for delivering anesthesia relative to retrobulbar and
peribulbar administration since it does not require sharp needles.
4.Intracameral injections
Intracameral route is similar to intravitreal injections but this injection delivers drug to the anterior
chamber. Drugs administered through this route are limited to anterior chamber with very limited
access to the posterior segment. It is generally employed for anterior segment procedures such as
cataract surgery.

22. B.CONTROLLED DRUG DELIVERY
1.Implants
Implants are devices that control drug release kinetics by utilizing various degradable or non-
biodegradable polymeric membranes. These are usually surgically implanted at the pars plana.
Polyvinyl alcohol (PVA), ethylene vinyl acetate (EVA), and polysulfone capillary fiber (PCF)
are most commonly used non-biodegradable implant polymers. PVA and EVA implants are
usually employed for delivering lipophilic drugs whereas PCF implants can be applied for
both hydrophilic and lipophilic molecules.
2.Gel systems
Gel formulations usually incorporate various phase changing polymers, i.e., after
administration, polymer phase changes into semi-solid or solid matrix in order to achieve
sustained drug delivery. Fluids showing viscoelastic nature are preferred for the usage in gel
forming systems. Such systems containing hyaluronic acid, polyacrylic acid and/or chitosan
are able to maintain high viscosity.

23. 3.Ocular inserts
The ocular inserts overcome this disadvantage by providing with more controlled,
sustained, and continuous drug delivery by maintaining an effective drug concentration in
the target tissues and yet minimizing the number of applications. It reduces systemic
adsorption of the drug. It causes accurate dosing of the drug.
4.Soluble ophthalmic drug insert
Soluble ophthalmic drug insert (SODI) is a small oval wafer, which was developed by
scientists for cosmonauts who could not use eye drops in weightless conditions. It is thin
sterile film of acryl amide, n-vinyl pyrrolidone. These can be used in treatment of
glaucoma.

24. C.MICRO AND NANO FORMULATIONS
1.Nano micelles
Nano micelles are the most commonly used carrier systems to formulate therapeutic agents in
to clear aqueous solutions. Tremendous interest is being shown towards development of Nano
micellar formulation based technology for ocular drug delivery. The reasons may be attributed
due to their high drug encapsulation capability, ease of preparation, small size, and hydrophilic
Nano micellar corona generating aqueous solution.

25. 2.Liposomes:
Liposomes are lipid vesicles with one or more phospholipid bilayers enclosing an aqueous
core. The size of liposomes usually range from 0.08 to 10.00 μm. These are biodegradable
and amphiphilic delivery systems usually formulated with phospholipids and cholesterol.
Liposomal formulations can be utilized for both improving the permeability as well as
sustaining the release of the entrapped hydrophilic drugs.
3.Nanoparticles/Nanospheres
Nanoparticles are colloidal carriers with a size range of 10 to 1000 nm. Drug loaded
nanoparticles can be Nano capsules or nanospheres. In Nano capsules, drug is enclosed
inside the polymeric shell while in nanospheres; drug is uniformly distributed throughout
polymeric matrix.

26. 4.Dendrimers
Dendrimers are characterized as nanosized, highly branched, star shaped polymeric
systems. These branched polymeric systems are available in different molecular
weights with terminal end amine, hydroxyl or carboxyl functional group. Dendrimers
are being employed as carrier systems in drug delivery.
5.Niosomes:
These are bilayer structures which can entrap both hydrophilic and lipophilic drugs.
These nonionic surfactant bilayers exhibit low toxicity and are chemically stable.
Noisome are also used in their modified form, i.e., discosomes (12-16 μm) in
ophthalmology.

27. D. PHYSICALAPPROACHES TO IMPROVE OCULAR
BIOAVAILABILITY: FORMULATION APPROACH
1.Viscosity enhancers
Polymers are usually added to ophthalmic drug solutions which increases the viscosity on the premise
and correspond to a slower elimination from the preocular area, which lead to improved precorneal
residence time and hence a greater trans corneal penetration of the drug into the anterior chamber. In
terms of improvement in bioavailability it has minimal effects in humans. The polymers used are
methylcellulose, polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), hydroxyethyl cellulose,
hydroxypropyl methylcellulose (HPMC), and hydroxypropyl cellulose.
2.Eye ointments
Ointments are usually formulated using mixtures of semisolid and solid hydrocarbons (paraffin) which
have a melting or softening point close to body temperature and are nonirritating to the eye. Ointments
may be simple bases, where the ointment forms one continuous phase, or compound bases where a
two-phased system (e.g., an emulsion) is employed.

28. 3.Penetration enhancers
By increasing the permeability of the corneal epithelial membrane the transport characteristics
across the cornea can be maximized, so to improve ophthalmic drug bioavailability. The
transport process from the cornea to the receptor site is a rate-limiting step, and permeation
enhancers increase corneal uptake by modifying the integrity of the corneal epithelium.
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 either chemically or enzymatically metabolized to the active parent compound.
Example; antiviral medications ganciclovir and acyclovir are the suitable prodrug.

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