This document discusses ocular drug delivery systems. It begins by defining an ocular drug delivery system as a novel approach where drugs are instilled in the eye's cul-de-sac cavity. It then describes the anatomy and barriers of the eye, including the anterior and posterior segments, tear film, and blood-ocular barriers. Various ocular drug delivery formulations are discussed such as inserts, vesicles, and controlled release systems. Barriers to ocular drug delivery like drainage, absorption, and permeability are outlined along with methods to overcome them like intravitreal injections. Ideal characteristics and factors affecting bioavailability of ocular delivery systems are also summarized.

1. Ocular Drug Delivery
System

2. • The novel approach of drug delivery in which the drug is instilled on
the cul de sac cavity of the eye (space between eyelids and eyeballs)
is known as Ocular Drug Delivery System.

3. • 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 sustain the drug
release and to remain in the vicinity of front of the eye for prolong
period of time.

4. The eye is a complex organ with unique anatomy and physiology.
The structure of the eye can be divided into two main parts:
the anterior segment and the posterior segment.
The anterior segment of the eye occupies approximately one-third while the
remaining portion is occupied by the posterior segment.
Tissues such as the cornea, conjunctiva, aqueous humor, iris, ciliary body, and lens
make up the anterior portion.
Back of the eye or posterior segment of the eye include; sclera, choroid, retinal
pigment epithelium, neural retina, optic nerve, and vitreous humor.

5. • The anterior and posterior segment of the eye is affected by
various vision-threatening diseases.
• glaucoma, allergic conjunctivitis, anterior uveitis, and cataract.
• Age-related macular degeneration (AMD) and diabetic
retinopathy

6. • Eye is composed of
• Water – 98%,
• Solid – 1.8%,
• Protein – 0.67%,
• Sugar – 0.65%,
• NaCl – 0.66%,
• other mineral element Sodium, Potassium and Ammonia –
0.79%.

8. Nasolachrymal drainage system
Nasolachrymal drainage system consists of three parts;
the secretory system,
the distributive system and
the excretory system.
The secretory portion is composed of the lacrimal gland that
secreted tears are spread over the ocular surface by the eyelids
during blinking.
The secretory system is stimulated by blinking and temperature
change due to the tear evaporation and reflux secretors that have
an efferent parasympathetic nerve supply and secrete in response
to physical and emotional stimulation e.g. crying.

9. The distributive system consists of the eyelids and the tear
meniscus around the lid edges of the open eye, which spread tears
over the ocular surface by blinking, thus preventing dry areas from
developing.
The excretory part of the Nasolachrymal drainage system consists
of the lachrymal puncta, the superior, inferior and common
canaliculi; the lachrymal sac, and the nasochrymal duct.
In humans, the two puncta are the openings of the lachrymal
canaliculi and are situated on an elevated area known as the
lachrymal papilla.
It is thought that tears are largely absorbed by the mucous
membrane that lines the ducts andthe lachrymal sac; only a small
amount reaches the nasal passage

10. Tearfilm
The exposed part of the eye is covered by a thin fluid layer, the so-
called precorneal tear film.
The film thickness is reported to be about 3–10 Am depending on
the measurement method used.
The resident volume amounts to about 10μl.
The osmolality of the tear film equals 310–350 mOsm/kg in
normal eyes and is adjusted by the monovalent and divalent
inorganic ions such as Na+, K+, Cl-, HCO3-, and proteins.
The mean pH value of normal tears is about 7.4.

11. • There 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, or
• used in conjunction with an ophthalmic device.

12. • The most commonly used employed dosage forms are the Solutions,
Suspensions, and Ointments.
• Topical administration is most popular and well accepted route of
administration
• The newest dosage forms are the
• Gels, Gel forming Solutions, Ocular inserts, intravitreal injections, and
implants.

13. • Mechanism of Ocular Drug Absorption
• Drugs administered by instillation must penetrate the eye and do so
primarily through the cornea followed by the non-corneal
routes.These non-corneal routes involve drug diffusion across the
conjunctiva and sclera and appear to be particularly important for
drugs that are poorly absorbed across the cornea

14. • Corneal permeation
• The permeation of drugs across the corneal membrane occurs from
the precorneal space. Transcellular transport occurs i.e. transport
between corneal epithelium and stroma.
• The productive absorption of most ophthalmic drugs results from
diffusional process across corneal membrane.
• Maximum absorption thus takes place through cornea, which leads
the drug into aqueous humor.
• Outer epithelium has only access to small ionic and lipophilic
molecules.

15. • Non-corneal permeation
• Primary mechanism of drug permeation is diffusion across sclera &
conjunctiva into intra ocular tissues.
• Although like cornea, the conjunctiva is composed of an epithelial
layer covering an underlying stroma, the conjunctival epithelium
offers substantially less resistance than does the corneal epithelium.
• This route is however, not productive as it restrains the entry of drug
into aqueous humor.
• This route is important for hydrophilic and large molecules, such as
insulin and p-aminoclonidine, which have poor corneal permeability.

16. Factors Affecting Intraocular Bioavailability
• Lacrimal fluids.
• Naso-lacrimal drainage.
• Interaction of drug with proteins of lacrimal fluids.
• Dilution with tears.
• Corneal barriers.
• Active ion transport at the cornea.

17. • Ophthalmic dosage forms are sterile products essentially free from
foreign particles, suitably compounded, and packaged for instillation
into the eye.
• Some of the dosage forms have been developed for Ocular drug
delivery systems.

18. Ocular Drug Delivery Systems

19. Advantages of Ocular Drug Delivery System
• 1. Increased accurate dosing. To overcome the side effects of pulsed
dosing produced by conventional systems.
2. To provide sustained and controlled drug delivery.
3. To increase the ocular bioavailability of drug by increasing the
corneal contact time. This can be achieved by effective adherence to
corneal surface.
4. To provide targeting within the ocular globe so as to prevent the
loss to other ocular tissues.
5. To circumvent the protective barriers like drainage, lacrimation and
conjunctival absorption.

20. Disadvantages of Ocular Drug Delivery System
• The residence time of the drug at the eye surface is less.
• Poor bioavailability.
• The instability of the dissolved drug.
• The low concentration of preservatives reduces shelf life after
opening the bottle.

21. Ideal Characteristics of Ocular Drug Delivery
System
• It should be sterile.
• It should be isotonic to body fluids.
• Buffer/pH adjustment.
• Less drainage tendency.
• Minimum protein binding.

22. Barriers to Ocular Drug Delivery System
• When a dosage form is either administered topically or systemically, it
faces multiple obstacles before it reaches its site of action. As
a result, ocular bioavailability from topically administered drugs is
usually only 1%-7% of the applied dose. These barriers can be broadly
classified as anatomical barriers and physiological barriers.

23. Barriers of Ocular Drug Delivery System

24. 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.

25. • 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. In general, the conjunctiva is leakier epithelium than the
cornea and its surface area is also nearly 20 times greater than that of
the cornea

26. 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
(The middle layer of the eye beneath the sclera. It consists of the iris, ciliary body,
and choroid).
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.
The posterior barrier between blood stream and eye is comprised of retinal
pigment epithelium (RPE) and the tight walls of retinal capillaries. Unlike retinal
capillaries the vasculature of the choroid has extensive blood flow and leaky walls.
Drugs easily gain access to the choroidal extravascular space, but thereafter
distribution into the retina is limited by the RPE and retinal endothelia.

27. • 3. Blood Ocular Barrier:
• This barrier normally keeps most drugs out of the eye, but
inflammation breaks down this barrier allowing drugs and large
molecules to penetrate the eye.
• (a) Blood aqueous barrier: The ciliary epithelium and capillaries of
the iris.
• (b) Blood retinal barrier: Non-fenestrated capillaries of the retinal
circulation and tight junctions between retinal epithelial cells
preventing passage of large molecules from choriocapillaris into the
retina.

28. • 2. Physiological Barriers:
• The eye’s primary line of defense is its tear film.
• The bioavailability of topically administered drugs is further reduced by
precorneal factors such as; solution drainage, tear dilution, tear turnover,
and increased lacrimation.
• This in turn lowers the exact time for absorption leading to reduced
bioavailability.
• Prevention: So, the drugs administered as eye drops need to be isotonic
and nonirritating to prevent significant precorneal loss.

29. Methods to Overcome Barriers to Ocular Drug
Delivery
• 1. Intravitreal Injections: Intravitreal injection (IVI) involves
delivering 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. Drug elimination occurs either through the retina
or the anterior chamber through the aqueous humor following a first-
order rate of decline.

30. This rate of elimination has a linear correlation with the molecular weight of
the drug. Larger molecules tend to have longer half-lives as high as several
weeks as compared to less than 3 days for low molecular weight compounds.
IVI administration is associated with adverse effects such as; retinal
detachment, cataract, hyperemia, and endophthalmitis.
Sustained release drug delivery systems can help by lowering the frequency of
administration and thus allow for better patient complianc

31. • 2. Subconjunctival Injections:
• This injection delivers the drug beneath the conjunctival membrane that
lines the inner surface of the 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.

32. • 3. Retrobulbar and Peribulbar Route: Retrobulbar injection is given
through eyelid and orbital fascia and it places the drug into
retrobulbar space. This mode administers the drug to the back of the
eyeball and is used to deliver drugs such as; antibiotics and
corticosteroids. This route is especially applicable for the delivery of
anesthetic agents as it causes minor or no change in IOP though in
certain orbital diseases the reverse is also possible. Yet, it is a very
delicate procedure as it may damage the optic nerve and thus
requires proper expertise and equipment.

33. • It is also a viable route for the delivery of anesthesia, especially in
cases of cataract surgery. It is a safer route compared to the
retrobulbar route with a reduced risk of injury. Though it is a safer
method, unlike retrobulbar injection multiple cases of elevated
intraocular pressure after peribulbar injections have been reported.

34. • 4. Sub-Tenon Injections: Sub-tenon injections are administered into a
cavity between the tenon’s capsule and sclera using a blunt cannula.
Pre-operative deep sedation is also not a requirement for this
procedure. The 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. Steroids
injected through this route have also been shown to be effective in
the treatment of uveitis, cystoid macular edema, complicating uveitis,
and non-necrotizing scleritis.

35. • 5. Intracameral Injections: Intracameral route is similar to intravitreal
injections, but this injection delivers the drug to the anterior
chamber. Drugs administered through this route are limited to an
anterior chamber with very limited access to the posterior segment. It
is generally employed for anterior segment procedures such as
cataract surgery. Clinical studies have reported that intracamerally
delivered dexamethasone is effective in reducing postoperative
inflammation in glaucomatous and non-glaucomatous patients. It is
an efficient and often more cost-effective method of delivering
antibiotics relative to topical antibiotics and antifungal agents.

36. Formulations for Ocular Drug Delivery System
• . Conventional Delivery Systems
• Eye drops
• Ointments and Gels
• Ocuserts and Lacriserts
• 2. Vesicular Systems
• Liposomes
• Niosomes and Discomes (Giant Niosomes)
• 3. Controlled Delivery Systems
• Implants
• Iontophoresis
• Dentrimer
• Microemulsion
• Nanosuspension
• Microneedle
• Mucoadhesive Polymers

37. Inserts
• Classification of Inserts
• Non-Erodible Inserts:
• (a) Ocusert
• (b) Contact Lens
• Erodible Inserts:
• (a) Lacriserts
• (b) SODI
• (c) Mindisc

38. 1. Non-Erodible Inserts:
(a)Ocuserts: It is a flat, flexible, elliptical device designed to be
placed in the inferior cul-de-sac between
(b) the sclera and eyelid which releases Pilocarpine continuously
at a steady state for 7 days. It comprises 3 layers:
1.Outer Layer: Ethylene-vinyl acetate copolymer layer.
2.Inner Layer: Pilocarpine gelled with alginate main polymer.
3.A retaining ring of EVA impregnated with titanium
dioxide. Example: Pilo 20 (20 mg/hr), Pilo 40 (40 mg/hr).

39. ocusert

40. b) Contact Lens: These are circular-shaped structures; dyes may
be added during the polymerization. Drug incorporation depends
on whether the structure is Hydrophilic or Hydrophobic.

41. 2. Erodible Inserts:
(a) Lacriserts: It is a sterile rod-shaped device composed of HPC without
preservatives. Its weight is 5 mg, its diameter is 12.5 mm and length is 3.5 mm.
It is used in dry eye treatment, Keratitis Sica.

42. (b) SODI (Soluble Ocular Drug Insert): Inserted in Inferior Fornix. It is a
small water-soluble wafer-like insert, composed of acrylamide vinyl
Pyrrolidone, Ethyl acrylate. It weighs 15-16 mg. It softens in 10-15 sec.,
turns in viscous liquids in 10-15 minutes, and after 30-60 minutes
becomes the polymeric solution. It is used in the treatment
of Glaucoma and Trachoma.

43. • (c) Minidisc: It is made up of a counter disc with a convex front and
concave back surface in contact with the eyeball. It measures 4-5 mm
in diameter. It is composed of silicon-based prepolymer. E.g.
Pilocarpine, Chloramphenicol.