FORMULATION OF OPHTHALMIC
• Ophthalmic preparations may be defined as;
“These are the sterile preparations intended for
installation into the eyes for the treatment of eye
diseases, for the relief of symptoms, for
diagnostic purposes, for washing of eyes & as an
adjuvant in the surgical procedures.”
• “These are the sterile preparation that are
compounded & packed for installation into the
• Drugs are commonly applied to the eye for the
localized effect of the medication on the
surface of the eye or on its interior. Most
frequently aqueous solutions are employed;
however non aqueous solutions, suspensions
& ophthalmic ointments are also commonly
used. Recently ophthalmic inserts,
impregnated with drug, have been developed
to provide for the continuous release of
medication. These inserts are of particular
usefulness for those drugs requiring frequent
day time & night time administration.
• Since the capacity of the eye to retain liquid &
ointment preparations is limited, they are
generally administrated in small volumes.
Larger volumes of liquid preparations may be
used to flush or wash the eye. The normal
volume of tears in the eye is 7µl, whereas a
non blinking eye can accommodate a
maximum of 30 µl of fluid, blinking eyes can
hold only 10µl.
• Excessive liquids both normally produced &
externally added are rapidly drained from the
eye. Thus the effective “dose” of medication
administered by ophthalmic route can be
varied by the
• strength of medication administered
• the volume administered
• the retention time of the medication in
contact with the surface of the eye
• the frequency of administration.
DRUGS WHICH ARE USED AS
• The major types of drugs used ophthalmically
are as follows:-
Miotics are used primarily in the treatment of
glaucoma. Miotics reduce intraocular pressure
associated with glaucoma. Among the miotics
are physostigmine, pilocarpine, neostigmine,
methacholine, carbachol etc.
2.Mydriatics & Cycloplegics:-
Mydriatics allow examination of the fundus of the
eye thought the dilatation of the pupil. The stronger
mydriatics having a long duration of action are
called cycloplegics. Among mydriatics & cycloplegics
are Atropine, hyoscyamine, scopolamine,
hematropine, Cocaine& cyclopentolate etc.
Local anesthetics allow for the relief of pain pre-
operatively, post operatively, following trauma
&during ophthalmic examination. Among the local
anesthetics used ophthalmically are Tetracaine,
benoximate, proparacaine, cocaine, dyclonine &
-These agents combat inflammation of the
eye. Most prominent among these are
hydrocortisone, prednisolone &
Local antiseptics are employed topically to
reduce microbial presence on the eye. Among
these are certain organic mercury compounds
as trimerosal & ammoniated mercury & silver
6. Anti-Microbial Agents:-
Antimicrobial agents are used
specifically to combat infection of
the eye. They are frequently
employed both systemically &
locally for their effect. Among those
applied topically to the eye are
sodium, Gentamycin, Tetracycline &
7. Astringents: -
These agents are generally used in the treatment of
conjunctivitis (inflammation of the conjunctiva
characterized by redness and often accompanied by
a discharge). Most preparations for this purpose
utilize Zinc-compounds, particularly Zinc Sulfate, as
8. Topical Protectants:-
These agents are employed as artificial tears
or as a contact lens fluid. Examples of agents
used in these solutions are methylcellulose &
• 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.
• 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
• 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
• The inside of the eyeball is divided by the lens into two
• The larger section at the back of the eye is filled with a
colorless gelatinous mass called the vitreous humor.
The smaller section in the front contains a clear, water-like
material called aqueous humor.
• The conjunctiva is a mucous membrane that begins at
the edge of the cornea and lines the inside surface of the
eyelids and sclera, which serves to lubricate the eye.
Absorption of drugs in the eye
Factors affecting drug availability:
1- Rapid solution drainage by gravity, induced
lachrymation, blinking reflex, and normal tear
- The normal volume of tears = 7 µl, the blinking eye
can accommodate a volume of up to 30 µl without
spillage, the drop volume = 50 ul
• The primary requirement for the ophthalmic
preparation is that it should be sterile. As most of the
ophthalmic preparations cannot be sterilized in the
final containers due to the sensitivity of the active
ingredients &/or excipients or package to the
elevated heat, therefore these products are sterilized
individually. They are blended aseptically, filled
aseptically in pre-sterilized containers using aseptic
capping technique. Due to these restrictions of
sterility & purity the ophthalmic products are
prepared in completely sterile environment using
aseptic techniques to minimize the chances of
contamination during the preparation & filling.
• Thus for the preparation of safe, sterile &
therapeutically active product, the following
factors must be controlled: -
• The environment required for the preparation of
ophthalmic product is same as that for parenterals.
Ophthalmic preparations are manufactured &
processed in aseptic area which needs the
requirements of class-100 space. Class-100 space is
an area having not more than 100 particles (living &
nonliving) larger than 25µm. Now this aseptic area is
constructed of hard, impervious material. The
ceiling, walls & floor are such that they can be
washed easily with disinfectant after each cycle.
• The air supplied to that area must be
sterile i.e. air is passed through the HEPA
Filters. A positive pressure is maintained
in the rooms (i.e. inside pressure is more
than outside) so that when the door is
opened the air flows outside rather than
coming inside. The personnel working in
that area must wear the sterile gowns,
gloves & foot covers. The inward &
outward traffic should be minimum.
2) MANUFACTURING TCHNIQUES
• In case of eye drops water soluble ingredients are
dissolved in water & then they are sterilized either by
heat or filtration process. In case of suspension,
which cannot be sterilized by filtration process, dry
powder is either heat sterilized or ethylene oxide or
by radiation. If dry powder is sensitive to heat &
radiation then it is dissolved in suitable solvent,
sterilized by filtration & then crystallized aseptically
.In case of ophthalmic ointments, the base is first
melted, heat sterilized & then filtered to remove
• Then pre sterilized active ingredients &
excipients are mixed aseptically with molten
base. Then this molten mass is passed through
sterilized colloidal mill & then it is filled in
previously sterilized container.
3) RAW MATERIALS:
The raw materials used for the ophthalmic
preparation (i.e. Active ingredients &
excepients) must be of highest purity &
quality. Specifications for the raw material of
every product should be established & each
lot of material purchased should be checked
for the established specifications
• Equipments used for the ophthalmic preparation
have same requirements as those used for
parenterals. All parts of the equipments coming in
contact with the product are made up of corrosion
free material, which can easily be disassembled,
cleaned & sterilized. Preferably they are made up of
high grade stainless steel. Moreover machinery used
should be cleaned regularly in order to avoid the risk
General safety considerations
- Ideally, all ophthalmic products should be
terminally sterilized in the final packaging.
- Only a few ophthalmic drugs formulated in simple
aqueous vehicles are stable to normal
autoclaving temperatures and times (121 C for
*Such heat-resistant drugs may be packaged in
glass or other heat-deformation-resistant
packaging and thus can be sterilized in this
Most ophthalmic products, however cannot
be heat sterilized due to the active principle
or polymers used to increase viscosity are
not stable to heat.
Most ophthalmic products are aseptically
manufactured and filled into previously
sterilized containers in aseptic
environments using aseptic filling-and-
B. Ocular toxicity and irritation
- Albino rabbits are used to test the ocular toxicity
and irritation of ophthalmic formulations.
- The procedure based on the examination of the
conjunctiva, the cornea or the iris.
- E.g. USP procedure for plastic containers:
1- Containers are cleaned and sterilized as in the
final packaged product.
2- Extracted by submersion in saline and
3- Topical ocular instillation of the extracts and
blanks in rabbits is maintained and ocular
• “Preservatives are the agents which preserve
the product by inhibiting the growth of
microorganism”. All ophthalmic solutions
should be sterile when dispensed.
Preservatives / Antimicrobials are used in
multi dose containers in order to inhibit the
growth of micro-organisms which may
contaminate the product during withdrawl of
Preservation and preservatives
• Preservatives are included in multiple-dose eye
solutions for maintaining the product sterility during
• The use of preservatives is prohibited in ophthalmic
products that are used at end the of eye surgery
otherwise they will cause irritation to the eye
So these products should be packaged in sterile, unit
dose containers and any unused solution is
• The most common organism is Pseudomonas
aeruginosa that grow in the cornea and cause loss of
Examples of preservatives:
1- Cationic wetting agents:
• Benzalkonium chloride (0.01%)
• It is generally used in combination with 0.01-0.1%
disodium edetate (EDTA). The chelating, EDTA has
the ability to render the resistant strains of
Pseudomonas aureginosa more sensitive to
2- Organic mercurials:
• Phenylmercuric nitrate 0.002-0.004%
phenylmercuric acetate 0.005-0.02%.
3-Esters of p- hydroxybenzoic acid:
• Mixture of 0.1% of both methyl and propyl
4- Alcohol Substitutes:
• Chlorobutanol(0.5%). Effective only at pH 5-6.
• Phenylethanol (0.5%)
Ideal ophthalmic delivery
systemFollowing characteristics are required to optimize
ocular drug delivery system:
• Good corneal penetration.
• Prolong contact time with corneal tissue.
• Simplicity of instillation for the patient.
• Non irritative and comfortable form
• Appropriate rheological properties
• “Vehicle is a medium in which the drug is dissolved,
suspended or emulsified & which functions to carry the
drug to the target site”.
• Some vehicles used in ophthalmic preparation are:-
i. For the ophthalmic drops purified water or normal
saline is used as vehicle. In some cases the viscosity
increasing polymers are also added to increase the drug
retention time in the eye.
ii. If a drug is sensitive to water or moisture then oils
are used as vehicles. Different oils used for this
purpose. The oil used should be of highest purity,
free from rancidity. The oil should be free from
antioxidant because antioxidants may be irritating to
iii. In the ophthalmic ointment, ointment base is used.
White petroleum is mixed with liquid petroleum to
produce the base of desired consistency. Some oil is
also used to decrease the melting point. This
petroleum base is widely used due to its anhydrous
nature & its inertness.
2) TONICITY MODIFIERS
• Tonicity modifiers are used to make the
ophthalmic solutions isotonic with the
lacrimal fluid. Body fluids, including blood &
lacrimal fluid, have an osmotic pressure
corresponding to that of a 0.9% solution of
NaCl. Thus a NaCl solution of this
concentration is said to be iso osmotic/
isotonic, or having an equal osmotic pressure
with physiologic fluids. The term isotonic
means “of equal tone or osmotic pressure”.
• The solutions with a lower osmotic pressure than
body fluids or a 0.9% NaCl solution are called
“Hypotonic” whereas solutions having a greater
osmotic pressure than body fluids are called
“Hypertonic”. Theoretically, a hypertonic solution
added to the body’s system will have a tendency to
draw water from the body tissues toward the
solution in effort to dilute & establish concentration
equilibrium. In eye, this solution could cause the
drawing of water toward the site of the topical
application. Conversely, a hypotonic solution might
induce the passage of water from the site of an
ophthalmic application through the tissue of the eye.
• Both of these conditions are undesirable. Thus
tonicity modifiers are used to adjust the
tonicity of the eye solutions. The agents used
for this purpose are NaCl, KCl, sucrose,
dextrose, PEG etc. In practice, the Isotonicity
limits of an ophthalmic solution in terms of
NaCl or its osmotic equivalent may range from
0.6 – 2% without marked discomfort to the
• “Buffers are the agents which resist change in
PH of the solution. "Buffers may be used in an
ophthalmic solution for one or all of the
1.To reduce discomfort to the patient.
2.To ensure drug stability & solubility.
3.To control the therapeutic activity of the
• Normal tears, having a PH of about 7.4,
possess some buffer capacity. The
introduction of a medicated solution into the
eye stimulates the flow of tears, which
attempts to neutralize any excess H+ or OH-
ions introduced with the solution. Normally,
the buffering action of the tears is capable of
neutralizing the ophthalmic solution & is
thereby able to prevent marked discomfort.
However a few drugs e.g. pilocarpine HCl are
quite acidic & overtax the buffer capacity of
the lacrimal fluid.
• For maximum comfort, an ophthalmic solution
should have the same PH as the lacrimal fluid
i.e. 7.4.The tolerable PH range is 6-8.Mostly
the drugs are most active therapeutically at
PH levels which favor the undissociated
molecule, because at this PH these are more
lipid soluble & hence are easily absorbed.
However the PH that permits greatest activity
may also be the PH at which the drug is least
• For this reason, a compromise PH is generally
selected for solution & maintained by buffers
to permit the greatest activity while
maintaining stability.PH also plays an
important role in the drug solubility. In
general, for acidic drug an increase in PH will
increase the solubility while for basic drug an
increase in PH will decrease the
solubility.(Because unionized form is less
• pH adjustment is very important as pH can:
1- render the formulation more stable
2- improve the comfort, safety and activity of
3- enhance aqueous solubility of the drug.
4- enhance the drug bioavailability
5- maximize preservative efficacy
• Viscosity is a property of a liquid that is
closely related to the resistance to flow.
The reciprocal of viscosity is fluidity. In the
preparation of ophthalmic solutions, a
suitable thickening agent is frequently
added to increase the viscosity & thereby
aid (help) in holding the drug in contact
with the tissues so as to enhance the
effectiveness. Generally methylcellulose,
hydroxypropyl methylcellulose & polyvinyl
alcohol are used as thickeners in ophthalmic
solutions. Viscosity for ophthalmic solutions is
considered optimal in the range of 15-25 Cps.
Definition: They 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
The most commonly employed ophthalmic dosage
forms are solutions, suspensions, and ointments.
These preparations when in-stilled into the eye are
rapidly drained away from the ocular cavity due to tear
flow and lacrimal nasal drainage.
The newest dosage forms for ophthalmic drug delivery
are: gels, gel-forming solutions, ocular inserts ,
intravitreal injections and implants.
Classification of ocular drug delivery
- Powders for
- Sol to gel systems
• “Ophthalmic solutions are sterile solutions
that are compounded & packed for
installation into the eyes. Ophthalmic
solutions may be aqueous solutions or oily
solutions. In addition to their sterility, their
preparation requires the careful consideration
of such other pharmaceutical factors as the
need for Antimicrobial agents, isotonicity,
buffering, viscosity & proper packaging
• Ophthalmic solutions provide more
uniform dosage forms, having better
bioavailability & greater ease for
handling during production. Ophthalmic
solutions are packed in containers with a
Disadvantages of eye solutions:
1-The very short time the solution stays at the eye
The retention of a solution in the eye is
influenced by viscosity, hydrogen ion
concentration and the instilled volume.
2- its poor bioavailability (a major portion i.e. 75%
is lost via nasolacrimal drainage)
3- the instability of the dissolved drug
4- the necessity of using preservatives.
2) OPTHALMIC SUSPENSIONS
• Ophthalmic suspensions are employed to a lesser
extent than are ophthalmic solutions; however
suspensions may be used to increase the corneal
contact time of a drug substance & thus provide
amore sustained action. Ophthalmic suspension may
be required when the drug is insoluble in the desired
vehicle or unstable in solution form. Ophthalmic
suspensions must also be sterile, with proper
consideration given also to preservation, isotonicity,
buffering, viscosity & packaging.
• Additionally ophthalmic suspensions must
contain particles of such chemical
characteristics & small dimensions that they
are non-irritating to the eye. Moreover the
suspended particles should not agglomerate
into larger ones upon storage. The suspension
must be shaken prior to use. Ophthalmic
suspensions are packed in the same types of
dropper container as are the ophthalmic
• Eyedrops have been packaged almost entirely in
plastic dropper bottles (the Drop-Tainer®
• The main advantage of the Drop-Tainer are:
- convenience of use by the patient
- decreased contamination potential
- lower weight
- lower cost
• The plastic bottle and dispensing tip is made of
low-density polyethylene (LDPE) resin, which
provides the necessary flexibility and inertness.
• The cap is made of harder resin than the
** Advantage of LDPE resin:
- Compatible with a very wide range of drugs
- and formulation components
** Disadvantage of LDPE resin:
- Sorption and permeability characteristics e.g.
volatile preservatives such as Chlorobutanol
- Weight loss by water vapour transmission
- LDPE resin is translucent, if the drug is light
sensitive, additional package protection is required
(using opacifying agent such as titanium dioxide)
-- LDPE resin sterilized by gamma irradiation or
• A special plastic ophthalmic package made of
polypropylene is introduced. The bottle is filled
then sterilized by steam under pressure at
• The glass bottle is made sterile by dry-heat or steam
• Amber glass is used for light-sensitive products
B. Semisolid Dosage Forms
• Ophthalmic Ointments and Gels:
• Ophthalmic ointments also increase the
ocular contact time of the drug.
Ophthalmic ointments, in contrast to
the dermatological (skin) ointments,
must be sterile. They are either
manufactured from sterilized
ingredients & under rigid aseptic
conditions or they are sterilized
• The ointment base selected for an ophthalmic
ointment must be non-irritating to the eye &
must permit the diffusion of the drug
throughout the secretions bathing the eye.
Ointment bases utilized for ophthalmic have a
melting or softening point close to body
temperature. Ophthalmic ointments are
packed in the previously sterilized tin or plastic
ophthalmic tubes, fitted with a narrow gauge
tips which permit the expulsion of narrow
bands of ointment.
- Ointments are used as vehicles for antibiotics,
sulfonamides, antifungals and anti-
- Petrolatum vehicle used as an ocular lubricant
to treat dry eye syndromes.
• Gels have increased residence time and
enhanced bioavailability than eye drops.
• Emulsion bases should not be used in the eye
owing to ocular irritation produced by the
soaps and surfactants used to form the
• It is suitable for moisture sensitive drugs and
has longer contact time than drops.
• Chlorobutanol and methyl- and
propylparaben are the most commonly used
preservatives in ophthalmic ointments.
• Ophthalmic inserts are defined as sterile solid or
semisolid preparations, with a thin, flexible and
multilayered structure, for insertion in the
• Recently ophthalmic inserts impregnated with
drug, have been developed to provide for the
continuous release of the drug. The insert unit is
designed to provide for the release of
medication at predetermined & predictable
rates permitting the elimination of frequent
dosing by the patient, ensuring night-time
medication & providing a better means of
• The insert is flexible & is a multilayered
structure consisting of a drug containing core
surrounded on each side by a layer of
copolymer membranes through which the
drug diffuses at a constant rate. The rate of
diffusion is controlled by the polymer
composition, the membrane thickness & the
solubility of the drug. The devices (inserts) are
sterile & do not contain preservatives.
• Increasing contact time and improving
• Providing a prolong drug release and thus a
• Reduction of adverse effects.
• Reduction of the number administrations and
thus better patient compliance.
C. Ocular Inserts
• Insoluble insert is a multilayered structure consisting
of a drug containing core surrounded on each side by a
layer of copolymer membranes through which the
drug diffuses at a constant rate.
• The rate of drug diffusion is controlled by:
- The polymer composition
- The membrane thickness
- The solubility of the drug
e.g. The Ocusert® Pilo-20 and Pilo-40 Ocular system
- 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 for
treatment of glucoma.
- consists of (a) a drug reservoir, pilocarpine (free base),
and a carrier material, alginic acid: (b) a rate controller
ethylene vinyl acetate (EVA) copolymer membrane.
• Advantages of pilocarpine
ocuserts over drops :
• The ocusert exposes the patient to a lower
amount of the drug leading to reduced side
effects .The ocusert provide a continuous
control of the intra-ocular pressure
The ocusert is administered only once per week
& this will imporve patient compliance .The
ocusert contain no preservative so they will be
suitable for patients sensitive to preservatives
in opthalmic solutions
Disadvantages of pilocarpine
• They are more expensive than drops
It may be inconvenient for the patient to retain
the ocusert in the eye for the full 7 days.
• The ocusert must be checked periodically by
the patient to see that the unit is still in place
D. Intraocular Dosage Forms
• They are Ophthalmic products that introduced into
the interior structures of the eye primarily during
• Requirements for formulation:
1- sterile and pyrogen-free
2- strict control of particulate matter
3- compatible with sensitive internal tissues
4-packaged as preservative-free single dosage
1- Irrigating Solutions
• It is a balanced salt solution was developed for
hydration and clarity of the cornea during surgery.