2. INTRODUCTION
Ophthalmic formulations are sterile products meant for instillation into the eye in the
space between the eyelids and the eyeballs.
Criteria for Selection of a Drug for Ophthalmic Use:
The drug must be bio-chemically and pharmacologically potent.
The drug must be non toxic to both ocular and systemic tissues.
The drug must be sufficiently stable that neither significant loss in potency from
diminished availability nor little increase in toxicity from byproducts of degradation
arises.
The drug can be either targetable to tissues and location of primary disease state
etiology or to sites responsible for symptomatic response.
The drug must be sufficiently compatible with the dosage form, and with the tissues
exposed to it, to achieve an effective pharmaco-kinetic tissue profile
3. INTRODUCTION
Loss of drug due to spillage: This takes place by spillage of drug from the eye and its
removal by the nasolacrimal drainage. The normal volume of tears in the human eye is
approximately 7-10 μl (if blinking occurs). The human eye can accommodate a volume of
up to 30 μl without spillage from the palpebral fissure. With an estimated drop volume of 50
μl, 70% of the administered volume of 2 drops can be seen to be expelled from the eye by
overflow. If blinking occurs, the residual volume of 10 μl indicates that 90% of the
administered volume of 2 drops will be expelled within a few minutes.
4. INTRODUCTION
Drainage: Drainage of the drop through the nasolacrimal system into the gastrointestinal
tract begins immediately on instillation. This takes place when either reflex tearing or the
dosage form causes the volume of fluid in the palpebral tissue to exceed the normal lacrimal
volume of 7-10 μl. The excess fluid volume enters the superior and inferior lacrimal puncta,
moves down the canalicula into the lacrimal sac, (as shown in fig) and continues into the
gastrointestinal tract. This also is the mechanism by which a patient may often sense a bitter
or salty taste, for example ammonium salts
5. INTRODUCTION
Superficial absorption: Superficial absorption of drug into the palpebral and bulbar
conjunctiva, with generally concomitant rapid removal from ocular tissues by the peripheral
blood flow also is an influencing factor
Transcorneal absorption: Often this route is most effective in bringing drug to the anterior
portion of the eye. Although transport of hydrophilic and macromolecular drugs has been
reported to occur by limbal or scleral routes, often this is at rates significantly reduced from
those expected for transcorneal transport of conventional, modestly lipophilic agents of low
molecular weight. Even here, transmembrane transport is a significant requirement for
availability
6. INTRODUCTION
REQUIREMENTS OF OPTHALMIC PREPARATIONS
1. Sterility and preservation
2. Tonicity
3. pH/Buffering
4. Surface activity
5. Clarity/foreign particles
6. Viscosity/thickening agents (15 cps to 25 cps)
7. INTRODUCTION
REQUIREMENTS OF OPTHALMIC PREPARATIONS
Sterility:
Ophthalmic solutions should be sterile when prepared, and care must be taken to
prevent contamination during use.
Ophthalmic solutions used during surgery or in the traumatized eye generally do not
contain preservative agents, because these are irritating to the eye. These solutions are
usually packaged in single-dose containers and any unused solution is discarded.
Ophthalmic solutions are most frequently contaminated by the organism Pseudomonas
aeruginosa. This is a very dangerous micro organism. It can cause complete loss of sight
within 24 - 48 hours. Contamination with a variety of other micro organisms is also
frequent
8. INTRODUCTION
REQUIREMENTS OF OPTHALMIC PREPARATIONS
Sterility:
A sterile multiple-dose ophthalmic solution can be contaminated in a number of ways if
precautions are not taken.
(a) If a dropper bottle is used, the tip of the dropper may touch the surface of a table or shelf.
(b) The tip can touch the eyelid or eye lash of the patient during administration.
Even though ophthalmic preparations are sterile, they must contain an effective, topically
non-irritating anti bacterial agent or a mixture of such agents. Preservatives prevent the
growth of, or destroy, micro organisms accidentally introduced in the preparation when the
container is opened during use. The preservative should be non-toxic, non-irritant, and
should be compatible with medicament
10. INTRODUCTION
Ophthalmic preparations are sterilized by any of the following techniques:
(a) Autoclaving
(b) Filtration
(c) Chemical sterilization
(a) Autoclaving: The most preferable method of sterilization is autoclaving of the final
containers. This method can be preferred if the ingredients of the preparation are
thermostable. Steam under pressure is commonly stated to kill all living organisms,
including spores and viruses. Following sterilization, pressure must be reduced slowly to
prevent bursting of bottles
11. INTRODUCTION
Ophthalmic preparations are sterilized by any of the following techniques:
(a) Autoclaving
(b) Filtration
(c) Chemical sterilization
(a) Autoclaving: The most preferable method of sterilization is autoclaving of the final
containers. This method can be preferred if the ingredients of the preparation are
thermostable. Steam under pressure is commonly stated to kill all living organisms,
including spores and viruses. Following sterilization, pressure must be reduced slowly to
prevent bursting of bottles
12. INTRODUCTION
Filtration: The advantage of the filtration is that, it is carried at room temperature and does
not cause or accelerate decomposition by heating. Buffering certain drugs near the
physiological range makes them quite unstable at high temperature. But the disadvantage is
that it does not remove or destroy viruses. Another advantage of the filtration is the retention
of all particulate matter, the removal of which is important in the manufacture and use of
ophthalmic solutions.
The filtration method involves transfer of solution into final containers after passage through
the filter. Filtration uses positive or negative pressure. It is essential to note that unless great
care is taken small amounts of drug can be trapped in the filtration assembly.
13. INTRODUCTION
Chemical sterilization:
Disadvantages are:
(a) This method does not destroy viruses.
(b) This method often requires considerable time to destroy bacteria and sometimes may be
quite ineffective. Antibacterial agents added in the preparation enhance the sterilizing
capacity of chemicals during sterilization.
For this method to use: (i) The glassware should be as nearly sterile as possible. (ii) All
solutions should be made with sterile distilled water. (iii) The solution should be dispensed
in a sterile container
14. INTRODUCTION
Tonicity:
Ophthalmic preparation must be isotonic with lachrymal secretions to avoid discomfort and
irritation. If hyper tonic solution is instilled into the eye, then the solution could cause the
drawing of water toward the site of the topical application. Conversely, a hypotonic solution
might induce the hemolysis of red blood cells, or the passage of water from the site of an
ophthalmic application through the tissues of the eye.
Active ingredient and other solutes added in the preparation contribute to the osmotic
pressure of the solution. If quantity of solution instilled is small, eyes can tolerate a certain
range of hypo/hyper tonicity. When quantity of solution instilled is large, adjustment of
tonicity is absolutely essential.
15. INTRODUCTION
Tonicity:
The freezing point of lachrymal fluid is – 0.052oC. 1g molecular weight of non electrolyte
is dissolved in 1000g of water to observe change in freezing point and thereby tonicity.
Therefore 61.8 g of boric acid (molecular weight of boric acid is 61.8 g) is dissolved in 1000
g of water. The freezing point of this solution is – 1.86oC. To calculate the quantity of boric
acid required to prepare isotonic solution, the following formula is used
16. INTRODUCTION
Tonicity:
Hence, 17.3 g of boric acid dissolved in 1000 g of water should produce a solution
isotonic with tears or blood.
For electrolytes, calculation is slightly different. E.g. sodium chloride solution. Assume
that sodium chloride in weak solutions dissociates up to about 80%. The 100 molecules
yield 180 particles. (80 particles of sodium + 80 particles of chloride + 20 particles of
undissociated sodium chloride).
To calculate the quantity of sodium chloride required to prepare isotonic solution, the
following formula is used
17. INTRODUCTION
Tonicity:
For example,
Molecular weight of sodium chloride = 58.5
Dissociation value (i) of Sodium chloride = 1.8
Molecular weight of Atropine sulphate = 695
Dissociation value (i) of Atropine sulphate = 2.6
695 × 1.8 / 58.5 × 2.6 = 1 g /x g
x g = 58.5 × 2.6/695 × 1.8 = 0.12
0.12 g of sodium chloride represents 1 g of atropine sulphate
18. INTRODUCTION
Tonicity:
For example,
For 30 ml solution of sodium chloride solution,
30 × 0.9 % = 0.27 g = 270 mg of sodium chloride
Concentration of Atropine sulphate present in the formulation is 1%
i.e. 1 g in 100 ml or 300 mg in 30 ml
0.12 × 300 mg = 36 mg
Thus, 270 – 36 = 234 mg of sodium chloride
20. INTRODUCTION
Ph and Buffers:
Buffers are used in an ophthalmic solution for the following reasons;
(a) to reduce discomfort to the patient.
(b) to ensure drug stability and safety.
(c) to control the therapeutic activity of the drug substance.
Normal tears have the pH of about 7.4. Tears possess some buffer capacity. The introduction
of an unbuffered medicated solution may cause irritation. This leads to increased secretion
of tears in an attempt to restore normal physiological condition.
21. INTRODUCTION
Ph and Buffers:
Most drugs used ophthalmically are weakly acidic (alkaloidal salts) and have only weak
buffer capacity. Therefore, the buffering action of the tears is sufficient to neutralize the
ophthalmic solution and is thereby able to prevent marked discomfort. For maximum
comfort, an ophthalmic solution should have the same pH as the lachrymal fluid (7.4).
However, this is not possible, because at this pH, many drugs are insoluble in water. For
example, alkaloidal salts are likely to precipitate as the free alkaloidal base at pH 7.4.
.
22. INTRODUCTION
Ph and Buffers:
Many drugs are most active therapeutically at pH levels which favour the unionized
molecule. Sometimes, the pH at which the drug is therapeutically active may be the pH at
which the drug is unstable. For this reason, a compromise pH is generally selected for a
solution and maintained by buffers to permit the greatest activity while maintaining stability.
The buffer system of an ophthalmic solution contributes to stability in another way by
preventing an increase in the pH of the solution due to the normal leaching by the solution
of alkali from the glass container.
.
23. INTRODUCTION
Surface Activity:
The vehicles used in ophthalmic preparations must have good wetting property.
Satisfactory wetting leads to increased penetration of the drug into the cornea and other
tissues. In order to achieve good wetting property, wetting agents or surfactants are added
These agents must be suitable for ophthalmic use and should not interact with any of the
ingredients of the ophthalmic preparation.
Benzalkonium chloride is most commonly used wetting agent. Because it also possesses
antimicrobial property.
Other surfactants are polysorbate 80, polysorbate 20, dioctyl sodium sulfosuccinate,
benzethonium chloride etc
24. INTRODUCTION
Clarity:
The ophthalmic solutions must be clear and free from foreign particles such as fibres and
filaments. The ophthalmic solutions are subjected to filtration to obtain desired clarity.
Bacteria proof filters such as membrane filters are used for filtration. These filters such as
membrane filters are used for filtration. These filters neither absorb any solution nor furnish
any fibres or particles to the filtrate. In case of ophthalmic suspensions, a separate filter
should be used for different ophthalmic products in order to avoid the contamination
25. INTRODUCTION
Viscosity:
To increase the time of contact of the drug with the eye, the viscosity of the preparation
is increased. Viscosity can be increased by using thickening agents. Examples include PVA,
PEG, MC, CMC etc. These should possess the following ideal properties:
(i) These should be easy to filter
(ii) These should be easy to sterilize.
(iii) These should be compatible with other ingredients.
(iv) These should possess requisite refractive index and clarity.
The thickening agents are not added in the formulation of eye drops and eye lotions that are
required to be used during or after surgery. Because these may cause some adverse effects
on the interior of the eye. Viscosity can be increased upto 15-50 cps. owever viscosity values
higher than this offer no significant advantages. Such high viscosities tend to leave a
residue on the lid margins