3 Formulation of ophthalmic ointments

and suspensions
The formulation of ophthalmic dosage forms requires safety to the eye, availability,
efficacy and pharmaceutical elegance, in addition to meeting the applicable regu-
lations [24]. Most ophthalmic preparations are available in sterile, buffered, isotonic
solutions, since the majority of ophthalmic drugs are water soluble. Solution dosage
forms are preferred as they are easy to administer. However, where the drug has limited
water solubility, or when a prolonged therapeutic action is required, disperse systems
such as suspensions, gelled systems and ointments are required. Ophthalmic dosage
forms are required to be manufactured to be sterile and to maintain sterility during
multiple applications.
The main characteristics of ophthalmic ointments, gelled systems and suspen-
sions are that they are non-irritating to the ocular tissues, homogeneous (uniform dis-
persion of particles and free from aggregates), non-greasy, should not cause blurred
vision, sterile, efficient and physically and chemically stable [24]. Gelled systems and
suspensions are generally aqueous systems (that do not cause blurred vision depend-
ing on the nature of dispersing and gelling agent), whereas ointments are oleaginous.
The formulation of ophthalmic suspensions and gelled systems follows the same rules
described for formulating suspensions for oral administration described above. These
include maintenance of colloid stability, absence of formation of strong aggregates,
absence of sedimentation and caking, and reduction of crystal growth. Any aggregates
produced can cause severe eye irritation. The main problems encountered in formu-
lating ophthalmic dosage forms are the difficulty in producing sterile drug particles
with the right size range, the difficulty in finding the optimum method for steriliza-
tion, formation of aggregates and separation of the liquid phase from the semisolid
ointment base on ageing [24].
Three general methods are applied for sterilization, namely autoclaving, heating
to 100 °C and filtration. Preservatives are included as major components of multi-
ple-dose ophthalmic suspensions, gels and ointments. The most commonly used
preservatives are benzalkonium chloride, chlorobutanol, thiomersal, methyl- and
propyl-paraben, chlorohexidine, phenyl ethanol and combinations of these chemi-
cals. Assessment of the ocular irritation potential of ophthalmic products represents
an extremely important step in the development of both over-the-counter (OTC) and
prescription ophthalmic ointments, gelled systems and suspensions. Albino rabbits
are generally used to test the ocular toxicity and irritability of ophthalmic formulations
and in most cases these in vivo tests are supplemented by in vitro methods [24].
The efficacy of drugs in ophthalmic formulations (their bioavailability) cannot
be measured directly by measuring their concentration in the ocular tissue fluids,
since sampling of the fluid causes severe ocular damage. With some drugs such as
mydriatics or miotics, the efficacy can be evaluated by measuring the change in pupil

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46 | 3 Formulation of ophthalmic ointments and suspensions

diameter. In the case of anti-glaucoma drugs, which are administered to control oc-
ular hypertension, the drug efficacy can be evaluated by monitoring the intraocular
pressure [24].
It is often assumed that drugs administered topically to the eye are rapidly and to-
tally absorbed and are available at a desirable site in the globe of the eye to exert their
therapeutic effect. However, this is not always the case since many systemically active
drugs such as atropine, hematropine and pilocarpine are applied at high concentra-
tions (5–10 %) to produce the desirable effect [24]. Absorption of drugs administered
as topical ophthalmics is affected by the nature of the eye, with its limited capacity to
hold the administered dosage forms, tear fluid and aqueous humour dynamics (se-
cretion and drainage rates), absorption by conjunctival tissues, penetration across
corneas and sclera, spillage, blinking rates and reflux tearing caused by administered
drug.
Drainage of the administered drop via the nasolacrimal system into the gastroin-
testinal tract begins immediately upon instillation. This takes place when reflux tear-
ing exceeds the volume of fluid in the palpebral tissues to exceed the normal volume
of 7–10 µl. The excess volume enters the superior and inferior lacrimal puncta, down
the canaliculus into the lacrimal sac, and then into the gastrointestinal tract. This is
illustrated in Fig. 3.1, which shows the anatomical view of the lids and lacrimal sys-
tem. It is due to this mechanism that significant systemic effects from certain potent
ophthalmic medications have been observed by several authors [24]. It is also the

Lacrimal gland
Excretory ducts

Canalicula Superior
lacrimal
puncta
Fornix
Inferior
lacrimal
puncta
Lacrimal
sac

Fig. 3.1: Anatomical view of the lids and lacrimal system.

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 3 Formulation of ophthalmic ointments and suspensions | 47

mechanism by which a patient may occasionally sense a bitter or salty taste follow-
ing use of eye drops.
Another mechanism competing for drug absorption into the eye is the superficial
absorption of the drug into the palpebral and bulbar conjunctiva with concomitant
rapid removal from the ocular tissues by peripheral blood flow. Underlying the con-
junctival mucous membrane is the sclera is the white part of the eye with its tough
covering, which forms the external protective coat of the eye along the cornea [24].
A schematic representation of the anatomical cross section of the anterior portion of
the human eye is shown in Fig. 3.2.

Anterior chamber
Cornea
Anterior chamber angel Canal of Schlemm

Conjunctiva Trabecular meshwork

Anterior ciliary vein

Sciera
Lens Ciliary muscle
Iris
Ciliary process
Posterior chamber Ciliary body
Suspensory ligament of lens
(zonule)

Fig. 3.2: Anatomical cross section of the anterior portion of the human eye.

In competition with the above mentioned forms of drug removal from the palpebral fis-
sure is the transcorneal absorption of the drug, i.e. that route most effective in bringing
the drug to the anterior portion of the eye via absorption. The cornea is an avascular
body and, along with the precorneal tear film, is the first refracting mechanism oper-
ant in the physiological process of sight. It is composed of three general layers, namely
lipid-rich epithelium, lipid-poor stroma and lipid-rich endothelium. The corneal ep-
ithelium and corneal endothelium each contain approximately 100 times as much
lipid as the corneal stroma. This is a primary physiological factor influencing drug
penetration through the cornea and into the aqueous humour. For a topically admin-
istered drug to traverse the intact cornea and to appear in the aqueous humour, it must
possess both hydrophilic and hydrophobic properties [24].
The transport of drugs across the cornea has been studied both in vivo and in
vitro. The in vitro studies are simpler to analyze than the in vivo absorption studies,
which are complicated by tear flow, tear drainage, corneal transport and elimination
from the aqueous humour. In addition, in vivo studies that require sampling of ocular

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48 | 3 Formulation of ophthalmic ointments and suspensions

fluids are not safe for patients. Several theoretical pharmacokinetic models were intro-
duced and a comparison could be made between the model prediction and the in vitro
results [24]. However, these in vitro results require a considerable number of in vivo
experiments to build adequate predictive models from molecular properties, such as
partition coefficient and molecular size, and this could help in designing molecules
with improved corneal penetration.
Several drugs are used for the topical treatment of various ocular diseases, e.g.
anti-glaucoma drugs (such as pilocarpine), anti-inflammatory agents (such as corti-
costeroids), anti-infectives (such as tobramycin), diagnostic agents (such as fluores-
cein), etc. Several other inactive ingredients are incorporated into ophthalmic sus-
pensions and gelled systems, e.g. buffers, stabilizers, surfactants, viscosity increas-
ing agents and osmolality adjusting agents. Ophthalmic ointments are prepared from
oleaginous bases composed of white petroleum, mineral oil and a special petrolatum/
polyethylene base. The drug is suspended in this oleogenic base using a dispersing
agent such as anhydrous lanolin, lanolin, polyoxy 40 stearate, polyethylene glycol
300, polyethylene glycol 400, cetyl alcohol and glyceryl monostearate. The antimi-
crobial preservatives used in ophthalmic ointments include methylparaben, propyl-
paraben, phenylethyl alcohol and chlorobutanol [24].
As mentioned above, all topical ophthalmic medications must be sterile. Unfortu-
nately the formulation cannot be subjected to normal autoclaving temperature (121 °C)
and time, since the active principle is not particularly stable either physically or chem-
ically on heating. Due to these product sensitivities all materials used for their formu-
lation must be sterile before use. The insoluble (or sparingly soluble) drug substance
is sterilized using dry heat, steam under pressure or ionizing radiation. Alternatively,
the drug may be dissolved in an organic solvent and filtered through inert, sterile
microporous membrane into a sterile receiver and thereafter be aseptically precipi-
tated from solution and maintained in a sterile condition through subsequent filtra-
tion and drying. Finally, the manufactured product is filled into previously sterilized
containers [24].
Apart from drug safety, stability and efficacy, the major design criteria of oph-
thalmic ointments, gel systems or suspensions is the additional safety criteria of steril-
ity and freedom from extraneous foreign particulate matter. This requires the use of
specially designed, environmentally controlled areas for the manufacture of large-
and small-volume injections for terminal sterilization.
The manufacturing techniques used for formulation of ophthalmic products are
determined by the type used. For simple ophthalmic solutions, complete dissolution
of the active ingredient and excipients must be ensured and this solution is sterilized
by heat or sterilizing filtration (using sterile membranes). This solution is then mixed
with the additional components, such as viscosity-imparting agents, preservatives,
etc. which must also be sterile. Aqueous ophthalmic suspensions are prepared by dis-
persing the sterile solid in water using a dispersing agent that is rendered previously
sterile by heat or ionizing radiation. Alternatively, the solid may be dissolved in an

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 3 Formulation of ophthalmic ointments and suspensions | 49

appropriate solvent and then go through sterile filtration and aseptic crystallization.
The sterile solid is then added to the batch either directly or by first dispersing the ster-
ile solid in a small portion of the batch. After adequate dispersion, this small sterile
portion can be readily added to the remainder of the batch, aseptically, with proper
aseptic rinsing. The batch is then brought to final volume with sterile water. Since the
eye is sensitive to large particles (20–25 µm) the particle size of suspended drug should
be 5–10 µm or smaller [24].
For the manufacture of an ophthalmic ointment, the raw materials components
must be rendered sterile prior to compounding, unless the ointment contains an aque-
ous component that can be sterilized by heat, filtration or ionizing radiation. The
ointment base is sterilized by heat and appropriately filtered while molten to remove
extraneous foreign particulate matter. It is then placed into a sterile steam-jacketed
kettle to maintain the ointment in a molten state under aseptic conditions, and the
previously sterilized microfine active ingredient and excipients are added aseptically.
While still molten, the entire ointment may then be passed through a previously steril-
ized colloid mill to adequately disperse the insoluble components. It is then filled into
sterilized containers [24].
All raw materials used in compounding ophthalmic pharmaceutical products
must be of the highest quality available. These raw materials are rendered sterile be-
fore compounding and the reactivity of the raw material with the sterilizing medium
must be evaluated and the sterilization must be validated to demonstrate its capability
of sterilizing the raw materials that contain large numbers (105 –107 ) of organisms that
may be resistant to the mode of sterilization. As mentioned above, the raw materials
used for suspensions must have a size range of 5–10 µm or smaller. The water used for
preparation of the suspension must also be sterile. This is achieved by distillation or
reverse osmosis and its storage and circulation at 80 °C in all steel equipment of the
highest attainable corrosion resistance quality [24].
The formulation of typical ophthalmic suspensions and ointments requires sev-
eral systematic steps. The first step (pre-formulation research that takes 1–2 years)
consists of generating a database for the drug substance, evaluating the compatibil-
ity of various excipients with the drug substance, developing a number of prototype
formulations from which a final, and if required a one or two back-up formulations,
are selected for further developments. The second step involves an early formula-
tion development (which takes 1–2 years) that is built on the pre-formulation data.
The emphasis at this stage is on screening a number of formulations with the ulti-
mate selection of a final formulation and one or two back-ups. Short-term accelerated
stability and compatibility of several formulations are established. Accelerated stud-
ies are typically performed at high temperatures considered to be stress conditions.
With suspensions and ointments, rheological investigations can be used to evalu-
ate and predict their physical stability (Chapter 14 of Vol. 1). The last step will be the
final development of the product including marketing, regulatory affairs, manufactur-
ing method, etc. In this final stage one has to consider the preparation of pilot plant

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50 | 3 Formulation of ophthalmic ointments and suspensions

and the process of scale-up of several batches to validate the manufacturing process.
Long-term stability studies must be conducted to confirm the shelf life of the product.
In addition, one must consider the efficacy of the product by carrying out clinical/
medical evaluation. Finally, toxicology studies must be carried out on the final formu-
lation to ensure absence of any adverse effects [24].

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