Ocular

1. Dr Athmar Dhahir Habeeb
PhD in Industrial Pharmacy and pharmaceutical formulations

2. The aim of any final dosage form is to deliver the drug molecule
in a therapeutic concentration to the site of action for an optimal
period of time.
Systemic drug distribution is often accompanied by side effects
due to off-target effects
Localised drug delivery to the site of action has the potential to
minimise the amount of dose needed for efficacy. Systemic side
effects can thus be minimised.
Certain modes of administration allow for localised treatment,
e.g. pulmonary, transdermal, nasal, rectal, vaginal, buccal and
ophthalmic routes

3. Drug delivery to the eye is one of the most important areas of
modern ocular therapy and presents many opportunities and
challenges.
Local drug delivery to the eye can in some cases be
accomplished, but there are major anatomical, biological and
physicochemical barriers that can limit efficacy
An understanding of the barriers associated with ophthalmic drug
delivery requires an understanding of the main parts of the eye
and the function of each part.
The eye consists of two compartments; the anterior segment
(which is the front of the eye) and constitutes 1/3 of the globe
while the other 2/3 of the globe is the posterior segment (which is
the back of the eye).
The eye is in direct contact with the environment and protected
by the eyelids, tear film and the cornea.

4. The cornea is a transparent layer that covers the front of the eye (iris,
which is the coloured part of the eye); it is highly innervated tissue with
no blood supply. It depends on the aqueous humour for nourishment and
removal of waste products. The front surface of the cornea is covered
with a tear film. The cornea consists broadly of three tissue layers each
separated by a membrane

5. The cornea is a complex barrier for absorption of drugs into the eye. In addition
to the cornea; tear turnover, nasolacrimal drainage and reflex blinking made
topical administration of medicines using eye drop is only really appropriate to
treat the periocular diseases.

6. The cornea is connected to the sclera through the limbus region. The sclera is the white
part of the eye that is tough in nature and is mainly comprised of collagen fibres. The sclera
is covered by a mucous membrane called the conjunctiva (which covers the inside of the
eyelid as well). The conjunctiva is a thin, transparent, mucous tissue that covers the front
of the eye, except the cornea. It is enriched with blood and lymph vessels that help to
nourish the ocular tissues. Its surface is covered by the mucus that helps to lubricate the
eye ball during movement and impart wettability to the ocular surfaces

7. The uvea comprises the iris, ciliary body, and the choroid plexus. The iris is the
coloured part of the eye. The anterior chamber is the space between the iris and
the cornea while posterior chamber is the space between the iris and the lens
(posterior to the iris and anterior to the lens); both are occupied by the aqueous
humour .The aqueous humour is a transparent fluid that fills the anterior and
posterior chambers .

8. The main parts of the posterior segment are vitreous humour, retina, choroid
and optic nerve. The vitreous humour is a clear viscous gel that fills the posterior
cavity of the eye. It is located between the lens and the retina.The retina is a
complex tissue that lies between the vitreous and sclera.The choroid is the
vascularised tissue comprising the blood-retinal-barrier and separates the retina
from the sclera. The blood-retinal barrier is considered the main key barrier for
the absorption of drugs into the posterior segment after systemic administration
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 uvea.
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.

9. schematic illustration of the main parts of the anterior and posterior segments,
barriers to ophthalmic drug delivery and routes of drug elimination from the
vitreous. The location of ophthalmic barriers (encircled in red) are; I) the cornea
and tear film; II) blood-retinal barriers; III) blood-aqueous barriers.
Routes of elimination from the vitreous (encircled in blue) are; 1) venous blood
flow after diffusing across the iris surface; 2) aqueous humour outflow; 3) diffusion
into the anterior chamber (1, 2 and 3 are referred to diffusion through the blood-
aqueous barriers); 4) diffusion through the blood–retinal barrier

10. *
*Dry eye syndrome.
*Ocular allergic conjunctivitis
*Postoperative inflammation
*Glaucoma.
*Uveitis.

11. Drug delivery to the anterior segment following systemic
administration is limited due to the blood–aqueous barrier,
Topical drug delivery to the eye
Topical drug delivery is the most convenient and efficacious method of
ocular drug delivery to the anterior segment.
The advantages of this route are obvious: it allows the drug to
selectively target the anterior chamber and it is non-invasive. However,
on a practical note, only 1 – 7% of the instilled drug reaches the
aqueous humor
Although the corneal route is assumed to be the principle route of
entry for topical drugs into the eye, studies have conclusively proved
that the conjunctiva–scleral layer also plays a role in the drug
absorption of large hydrophilic molecules.
The permeability of the conjunctiva to large hydrophilic molecules is
in fact twice that of the sclera and higher than the cornea
This route is generally less productive

13. Following characteristics are required to optimize ocular drug delivery
system:
a. Good corneal penetration.
b. Prolong contact time with corneal tissue.
c. Simplicity of instillation for the patient.
d. Non irritative and comfortable form (viscous solution should not
provoke lachrymal secretion and reflex blinking)
e. Appropriate rheological properties and concentrations of the viscous
system.

14. A) Reducing drug drainage
1. Punctal plug occlusion helps to reduce drug absorption by the large
nasal mucosa and to decrease side effects.

15. 2- Increasing drug penetration through the epithelium
(penetration enhancers such as benzalkonium chloride)

16. 3- Iontophoresis is a technique of introducing drugs into tissues
noninvasively, by imposing electric currents across the cornea or sclera.
Transcorneal iontophoresis has shown enhanced drug penetration into
the aqueous
Iontophoresis is a new concept in ocular drug delivery system in which
charged drug molecules are used. Positive charge drug molecules were
driven into the tissue at anode and negative charge drug molecule
driven respectively at cathode. Ocular Iontophoresis is safe, fast and
easy. It is also proficient to hold high concentration of drugs at targeted
tissue. Ocular Iontophoresis delivery is not only fast, painless and safe
but it can also deliver high concentration of the drug to a specific site

17. B) Increasing retention time in the conjunctival cul-de-sac
Ophthalmic ointments are emulsions of aqueous drugs and
ointment bases (e.g., white petroleum).
The major advantage is their tendency to serve as a drug depot in
the conjunctival sac, resulting in enhanced and sustained drug
absorption.
The disadvantages include blurring of vision on instillation,
difficulty in applying the exact dose, and sensitivity of the base to
temperature.
Increasing viscosity of solutions
The viscosity of ophthalmic solutions can be increased by
methylcellulose, hydroxypropylmethycellulose, hydroxyethyl
cellulose and poly(vinyl alcohol) (PVA) among others. They
increase the residence time of the drug and slow clearance,
resulting in enhanced absorption. Patton and Robinson
Higher viscosity caused ocular surface irritation, increased blinking
and higher drainage. A more viscous solution also causes visual
blurring and may block the puncti and canaliculi.

18. Mucoadhesive formulations
Mucoadhesion refers to the process of attachment of the drug
carrier system to the mucin coat covering the conjunctiva and
cornea.
Mucoadhesives increase the residence time and, in addition,
provide intimate contact between the drug and the absorbing
tissue, which results in a high drug concentration in the local area
and a high drug flux through the absorbing tissue.
The most commonly used mucoadhesives are macromolecular
hydrocolloids that cannot cross biological membranes
Hyaluronic acid is a mucoadhesive biological polymer that also has
the advantages of having a high water binding capacity, non-
irritancy, increased viscosity and pseudoplastic behaviour

19. Gels and inserts
In situ gel-forming systems are formulations that undergo gellation on
contact with the ocular system. They combine the advantages of
dispensing an aqueous solution with increased retention time of a high-
viscosity formulation.
Ophthalmic inserts are solid devices that are placed in the conjunctival
cul-de-sac. These devices are designed to release the drug at a constant
rate for a prolonged duration of time whilst minimising systemic
absorption through the nasal mucosa and improving patient compliance.
They are divided into biodegradable and non biodegradable inserts

20. Non biodegradable:The pilocarpine Ocusert® (ALZA Corp.) was
the first marketed device to achieve zero-order kinetics. The
drug is contained in a reservoir enclosed by two release-
controlling membranes made of ethylene vinyl acetate
copolymer and surrounded by a ring to aid in the positioning and
placement.
Biodegradable: Lacisert It is a sterile rod shaped device made
up of hydroxyl propyl cellulose without any preservative is used
for the treatment of dry eye syndromes

21. Therapeutic contact lenses
Soft contact lens-based DDSs have been investigated by several
approaches: (1) Soak and absorption of drug solution (2) piggyback
contact lens combined with a drug plate or drug solution (3)
surface-modification to immobilize drugs on the surface of
contact lenses (4) (incorporation of drugs in a colloidal structure
dispersed in the lens (5) ion ligandcontaining polymeric hydrogel
and (6) molecularly imprinting of drugs.

23. Microparticles
Liposomes are biocompatible and biodegradable lipid vesicles 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
partition coefficient, poor solubility or those with medium to high
molecular weights and thus increases the probability of ocular drug
absorption. The potential advantage achieved with the liposome have
been have been the control of the rate of encapsulated drug and
protection of drug from metabolic enzymes present at tear corneal
epithelium surface.

24. Microparticles
Niosomes Niosomes are nonionic surfactant vesicles that have potential
applications in the delivery of hydrophobic or amphiphilic drugs. The
major limitations of liposomes are chemical instability, oxidative
degradation of phospholipids, cost and purity of natural phospholipids.
To avoid this niosomes are developed as they are chemically stable as
compared to liposomes and can entrap both hydrophobic and hydrophilic
drugs. They are non toxic and do not require special handling
techniques.

25. Dendrimers
Dendrimers are successfully used for different routes of drug
administration and have better water-solubility, bioavailability
and biocompatibility.
Dendrimers are a unique class of synthetic macromolecules that
can be distinguished from classical linear polymers by their
highly branched, monodispersed, circular, and symmetrical
architecture
Microemulsion
Nanosuspension
Prodrug

26. Nanoparticles
The polymeric nanoparticulate system comprises particles in the
range of 1–1,000 nm in which the parent drug is adsorbed,
entrapped, conjugated, or encapsulated. The nanoparticulate
system can be an alternative to address irritation and toxicity
related issues of liposomes and dendrimers. Aqueous or
nonaqueous suspension of drug-loaded nanoparticles can be
administered in the cul-de-sac to achieve sustained drug delivery,
which can eliminate frequent drug administration. Moreover, the
active drug can be slowly released by diffusion, dissolution, or
mechanical disintegration and/or erosion of the polymer matrix.
Nanoemulsion
Nanoemulsion offers several advantages in ocular drug delivery,
such as high capacity to dissolve both hydrophilic and lipophilic
drugs, stability, improved bioavailability, and good spreadability.
In addition, surfactants used in formulating emulsions can also act
as penetration enhancers, thereby improving drug permeability
across the cornea.

27. Subconjunctival drug delivery (injections and implants)
The subconjunctival route is an attempt to minimise dosing
frequency while maintaining a sustained drug delivery to the
anterior and posterior segment over a prolonged duration of time.
However, the morbidity of repeated subconjunctival injections,
particularly in inflamed eyes, has reduced the popularity of this
route for anterior segment drug delivery.
Placing injections subconjunctivally bypasses the lipid layers of
the bulbar conjunctiva and places the drugs adjacent to the
water-permeable sclera, increasing water-soluble drug
penetration into the eye. Local leakage also allows corneal
penetration
Subconjunctival/episcleral implants have the advantages of direct
delivery of medication into the eye, fewer adverse events than
systemic delivery, and better patient compliance than topical eye
drops. They are usually inserted with a small incision in the
conjunctiva and placed in direct contact with the sclera

28. Advantages
*Markedly increased penetration of water soluble drugs.
*Short term high concentrations of drugs in cornea and anterior segment.
*Supplement to topical therapy.
Disadvantages
*Local irritation, residues, necrosis and granuloma formation can occur at
the site of injection.
*Once injected the drug(s) cannot be removed.
*Temporary pain at site of injection.
*Injection is quite difficult with potential of injury to eye.

29. Surodex is a rod-shaped biodegradable poly(dl-lactide-co-
glycolide) (PLGA) matrix implant (1.0 · 0.5mm) consisting of
dexamethasone (60 mg) and PLGA with hydroxypropyl
methylcellulose, which provides sustained drug release at a
constant rate over 7–10 days.26 The implant is inserted into
the anterior chamber after cataract surgery to control
postoperative inflammation.
Glaucoma drainage devices
GDDs are implants used to create an alternative aqueous
drainage pathway from the anterior chamber. A new drainage
channel is formed by the tube to direct the aqueous flow into
the subconjunctival space

31. Ion-exchange resin
The drug (acidic or basic in nature) is ionically bound to an ion-exchange resin to
form an insoluble complex. Drug can only be released from the complex through
exchange of the bound drug ions with physiological ions in body fluids. The actual
resin is an insoluble
Betaxolol hydrochloride (a cardioselective betablocker) is available as an ion-resin
suspension formulation (Betoptic-S®, Alcon, US). The positively charged drug is
bound to a cation-exchange resin (Amberlite® IRP69). The matrix of Amberlite
IRP69 is styrene-divinylbenzene polymer and the functional portion is sodium
polystyrene sulphonate. Sulphonic acid acts as a strong cation exchanger. The
mobile, or exchangeable, cation is sodium; this can be exchanged for many
cationic species. Upon ocular instillation of the suspension, betaxolol is displaced
from the resin by the sodium ions in the tear film