Ophthalmic Preparations

Absorption
Of
Drugs

Corneal
Absorption

Non Corneal
Absorption
 Corneal Absorption
More effective than sclera or conjunctival
absorption in which removal by blood vessels
into general circulation occurs.
Ophthalmic drugs are weak bases &are applied
to the eye as aqueous solutions of their salts.
 Steps of Absorption of a Weak Base Drug:
1.Free base & its salt will be in an equilibrium.(according to pH &
individual characteristics of drug molecule)

2. Once inside the corneal epithelium, undissociated free base

dissociates immediately to a degree.
3.Dissociated moiety penetrates the stroma.(water soluble)

4. At the junction of the stroma & the endothelium the same

process that took place at the outer surface of the epithelium
must occur again.
5.Finally,dissociated drug leaves the endothelium for the
aqueous humor. Here it can readily diffuse to the iris and the
ciliary body, the site of its pharmacological action.
N.B.
To aid in maintaining storage stability & solubility, the medication
may be acidic at the moment of instillation but, usually, the
neutralizing action of the lacrimal fluid will convert it rapidly to
the physiological PH range (around 7.4) at which there will be
enough free base present to begin penetration of the corneal
epithelium.
 Problems encountered with corneal absorption:
Barriers encountered in ocular drug delivery are:
(a) Short residence time in the precorneal area.
(b) Poor permeability of the cornea.

Possible solutions vehicle modification,

bioadhesives, penetration enhancement.
(Examples of some penetration enhancers: cyclodextrin, saponin, -amino
acid)
 Non corneal Route of Absorption

Significant for poorly cornea permeable drugs.

e.g. inulin, timolol maleate & gentamicin
These drugs gain intraocular access by diffusion
across the conjunctiva & sclera.

Disadvantage drugs continuous removal by

blood vessels into the general circulation.
 Requirements of Ophthalmic
Preparations
Clarity:
Ophthalmic solutions are free from foreign
particles.
Clarity is normally achieved by filtration.
Preparation must be done in clean surroundings.
Use of laminar flow hoods will contribute
collectively to the preparation of clear solution free
from foreign particles.
(In many instances clarity and sterility may be achieved in the same filtration step)
Stability
Stability refers to total product stability and not just the
chemical stability of a single component in the product.

Drugs such as pilocarpine & physostigmine are both

active & comfortable at a PH of 6.8. Yet at this PH, chemical stability
can be measured in days or months only.
On the other hand, at PH 5 both drugs are stable for a
period of several years & on adminstration, they are
buffered by physiological buffers in eye to PH 6.8.

In addition to PH, if the drug is liable to oxidation, then

adequate stability may require the inclusion of an
antioxidant as sodium bisulfate, or metabisulfite. The
antioxidant here acts as stabilizer.
Buffer & PH:
Ideally, ophthalmic preparations should be
formulated at a pH equivalent to the tear fluid
value of 7.4.
Practically, this rarely happens as the majority of
active ingredients used in ophthalmology are salts
of weak bases & are most stable at acidic PH.
Others which require an acidic PH such as
suspensions of insoluble corticosteroids cannot be
formulated at this PH.
PH selected should be optimum for stability.
 upon instillation,
If the overall PH of the tears reverts rapidly to PH
7.4, discomfort is minimal.
If the buffer capacity is sufficient to resist adjustment
by the tear fluid & changed the overall eye PH,
then stinging & discomfort may result.

Conclusion: buffer capacity should be adequate for

stability, but minimized so far as possible, to allow
overall PH f the tear fluid to be disrupted only
momentarily.
Tonicity:
Tonicity refers to the osmotic pressure exerted
by salts in aqueous solution.
An ophthalmic solution is isotonic when its
tonicity is equal to that of 0.9% NaCl. (eye can tolerate
solutions equivalent to a range of 0.5-1.8% NaCl)

Tonicity adjusting agents used include sodium

chloride, potassium chloride, buffer salts,
dextrose, glycerin, & propylene glycol.
Viscosity:
USP permits use of viscosity increasing agents to
prolong contact time in the eye & thus enhance
drug absorption &activity.
e.g. methylcellulose, polyvinyl alcohol, & hydroxyl propyl
methylcellulose.

Theses polymers tend to dry to a film on the eye

lids; whichcan be removed by whipping with a
damp tissue.
Viscosity increased up to the 15 to 50 cps range
significantly improves contact time in the eye.

Results tend to plateau beyond the 50- cps ; higher

viscosity values offer no significant advantage &
leave a noticeable residue on the lid margins.
 Sterilization

Steam under
Radiation
Pressure

Gas
Filtration
Sterilization
1. Steam under Pressure:
Acceptable, effective method of sterilization.
Solution or suspension components must be sufficiently
heat resistant.
If sterilization is carried out in the final container, the
container also must be able to survive the heat &
pressure.
A recent addition to this technique is air-over-steam
autoclave in which pressure adjustments are made
during the autoclave cycle. Wet heat is more effective
than dry heat. Therefore, autoclaving (115-130C) is used
in terminal sterilization if the product or container
doesnt withstand hot air sterilization (over250C).
Pressure manipulations permit the autoclave sterilization
of materials which tend to deform in shape when heated
as propylene containers.
2. Filtration:
The USP states that sterile membrane filtration under aseptic
conditions is the preferred method of sterilization.
Membrane filtration offers the advantage of room
temperature operation with none of the deterioration effects
of exposure to heat or sterilizing gas.

3. Gas Sterilization:
Carried out by exposure to ethylene oxide gas in the presence
of moisture.
Ethylene oxide sterilization produces irritating by-products
that remain as residues in or on the items sterilized. Residues
include ethylene glycol and ethylene chlorohydrins in addition to ethyleneoxide itself.

To minimize such residues the sterilized items should be

aerated for at least 72 hr, preferably at 40-50.
4. Radiation:
Acceptable procedure for components of ophthalmic
preparations, or total product, such as ophthalmic ointments.

Sources of radiation include linear electron accelerators &

radioisotopes.

Linear accelerators produce high-energy electrons with very

little penetrating power.
Radioisotopes, particulary60Co, are employed.

May produce unwanted effects such as chemical changes in

product components & chemical changes in characteristics of
package components.
Preservation & Preservatives:
Included in multiple dose eye solutions for
maintaining sterility of the product after opening &
during the use unless prepared in a unit-dose
package.
Use of the popular plastic eye drop container has
reduced the chances of inadvertent contamination
but not completely. WHY?
1. As a suck-back of an unreleased drop when
pressure on the bottle is released.
2. Also if the tip was allowed to touch a non sterile
surface then contamination could be introduced.
Criteria in preservative selection:
Acts against broad spectrum of bacteria (gram-positive & gram-
negative) as well as fungi.
Exerts a rapid bactericidal activity, particularly against Pseudomonas
aeruginosa strains.
Stable over a wide range of conditions including autoclaving
temperature & PH range.
Compatible other preparation components &with package system.
Lack of toxicity & irritation should be established with a reasonable
margin of safety.

Actually, only a few chemicals have been found over the years to be safe
and effective for this purpose.
These are benzalkonium chloride, chlororbutanol, phenylmercuric nitrate &
acetae,thimerosal, methyl &propyl paraben, phenyl ethanol & various
combinations of these chemicals.
Benzalkonium Chloride (Quaternary Ammonium
Compounds):
Used in combination with disodium editate in conc. 0.001%-0.1%.WHY?
The mechanism of bactericidal/ action is thought to be due to disruption of
intermolecular interactions. This can cause dissociation of cellular membrane lipid
bilayers,
It has excellent chemical stability & very good antimicrobial
characteristics.

Limitations: its cationic surface active material of high molecular weight,

not compatible with anionic compounds such as salicylates & may be
inactivated by high molecular weight non ionic compounds.
Another quaternary ammonium germicide, benzethonium chloride, has been
used in several ophthalmic solutions. Benzethonium chloride exhibits a broad
spectrum of microbiocidal activity against bacteria, fungi, mold and viruses.
Organic Mercurials:
If benzalkonium chloride cannot be used in a
particular formulation, as with pilocarpine nitrate,
phenyl mercuric nitrate (PMN), phenyl mercuric
acetate (PMA), or thimerosal, is used.
Mercurials have been found to be relatively weak &
slow in their antimicrobial activity.
Mercurials are restricted to use in neutral to alkaline
solutions; yet they have been used successfully in
slightly acid PH formulations.
Phenyl mercuric nitrate has the advantage over some other organic
mercurials of not being precipitated at a slightly acid PH. Phenyl
mercuric ion is incompatible with halides, as it forms precipitates.
Chlorobutanol:
Effective preservative & is used in several ophthalmic products.
It possesses antibacterial activity against both gram positive & gram
negative microorganisms including Pseudomonas aeruginosa strains.
One of its hydrolysis products is hydrochloric acid, which causes decrease
in the PH of aqueous solution.
Decomposition occurs:
1. Rapidly at high temperature & slowly at room temperature
2. In unbuffered solutions that were originally neutral or alkaline.
Ophthalmic solutions containing chlorobutanol should be buffered between
PH 5 & 5.5.
At room temperature it dissolves slowly in water.
Although it dissolves more rapidly on heating, loss by vaporization and
decomposition is accelerated.

A combination of chlorobuatnol & phenylethyl alcohol (0.5% of each) has been reported to be more effective
against Pseudomonas aeruginosa, Staphylococcus aureus, & Proteus vulgaris than either antimicrobial
singly
 Solid Dosage Forms
Ocular Inserts

In early times lamella or disks of glycerinated

gelatin were used to supply drugs to the eye by
insertion beneath eye lid.
Aqueous tear fluids dissolve the lamella & release
the drug for absorption.
Cotton pled gets soaked in drug solution were
used to deliver drugs to the eye.
 Non erodible Ocular Inserts
In 1975, the first controlled release topical dosage form was
marketed in the United States by the Alza Corporation which was
pilocarpine ocusert.
Pilocarpine ocusert is an elliptical- shaped membrane which is
soft & flexible designed to be placed in the cul-de-sac between
the sclera & the eye lid .
Pilocarpine ocusert consists of :
( 1) Drug reservoir,pilocarpine, carrier material, alginic acid.
(2) A rate controller, ethylene vinyl acetate (EVA) copolymer
membrane.
(3) An energy source, the concentration of pilocarpine in the
reservoir.
(4) A delivery portal, the copolymer membrane.
 Advantages over drop therapy for the glaucoma patient:
1. Exposes the patient to only one-fourth to one-eighth the amount of pilcarpine
compared to drop therapy. (reduced local side effects & toxicity.)
2. It provides a continuous around the clock- control of IOP.
3. Patient convenience & improved compliance.(administered only once
per week.)

Patient must check periodically that the unit is still in

place, particularly in the morning upon arising.

It is doubtful that the ocusert will replace the standard

drop therapy for glaucoma, but it will offer the physician
an alternate means of therapy for certain patient groups
such as those who are sensitive to the preservatives in
ophthalmic solutions, those who do not have the
competency to instill drops, & those who cannot tolerate
some
 Soft Contact Lens

Soft hydrophilic contact lens of the hydroxyl ethyl methacrylate

(HEMA) type polymer to prolong delivery of pilocarpine.
Lens is presoaked in a sterile unpreserved solution of the drug.

Placed in the eye over the cornea for a period of time, usually few
minutes to several hours to increase the amount of drug absorbed
or to prolong the duration of effect.(reduce the frequency of drug instillation &
give diurnal control to the treatment of glaucoma)

Uncontrolled nature to the release of drug from it.

Potential for increased risks of contamination since
unpreserved drug solutions must be used & the
patient must disinfect the lens himself.
 Erodible Ocular Inserts
Contain polymers, when dried they form films of polymer drug system.

These films inserted in the cul-de-sac to:

a) Increase retention time. b) Increase penetration of the drug

Acts by absorbing the aqueous tear fluid & then gradually erodes or
disintegrates.

Drug is slowly leached from the matrix & then after certain period of time
this lens loses its solid integrity & is squeezed out of the eye with eye
movements & blinking.

Provide an uncontrolled release of drug but do prolong contact time.

Advantage over the non erodible membrane or soft contact lens inserts is
that they dont have to be removed at the end of the therapy.
 Subconjunctival Injections

Introduce medications that if applied topically either:

a)Do not penetrate into the anterior segment.
b)Penetrate too slowly to attain the concentration required.

Drug is injected underneath the conjunctiva & passes through the

sclera & into the eye by simple diffusion.

Used for the administration of antibiotics in infections of anterior

segment of the eye.
 Iontophoresis
Def.: use of a direct electrical current to drive topically applied
ionized substances into or through a tissue. Iontophoresesis based
on the physical principle that ions with the same charge repel and
ions with opposite charge attract.
Drug solution or preparation to be iontophorised should be devoid
or have minimum of extraneous ions.
Drugs with one or more pKa values either below pH 6 or above pH8
are excellent candidates for iontophoreses into the eye because
these drugs will be in the ionized form at physiological pH of the
eye.

The salt form of a drug is also preferred for iontophoreses since the
dissociated salt is highly soluble.
 Principle of Iontophoresis:
Drug is driven into the ocular tissue with
an electrode carrying the same charge as
the drug.

Ground electrode (opposite charge) is

placed elsewhere on the body(usually the
ear) to complete the circuit.

The drug or bioactive substance serves as

a conductor of the current through the
ocular tissue.

The transported drugs or bioactive

substance either remains in the tissue
until they are altered /metabolized or are
carried away by the blood vascular
network.
 Mucoadhesive Polymers

Provide a localized delivery of medicinal agents to a specific site in

the body.

Improve ocular bioavailability.

Intimate contact may result in high drug concentration in the local

area & hence high drug flux through the absorbing tissue.

The intimate contact may also increase the local permeability of

high molecularweighrt drugs such as peptides and proteins.
 Contact Lenses
Contact lenses are optical and/or therapeutic ophthalmic devices
which are divided into four general categories:
(a) Rigid hydrophobic, so- called hard contact lenses.
(b) Soft, flexible and hydrophilic.
(c) Flexible , hydrophobic.
(d) Rigid hydrophilic.

Each lens is accompanied by its support solution products & devices.

Lens materials & support products are further classified & identified in
table.