Lecture 4

Ocular Dosage Forms

By
Dr/ Ahmed Shawky Srag El-Din
Lecturer of Pharmaceutics and Industrial
pharmacy
 Ocular Dosage Forms
➢Sterile, isotonic (0.7 and 1.5% w/w NaCl) DF that used to treat ocular disorders, e.g., infection,
inflammation, intraocular disorders and glaucoma.
➢Ocular dosage forms are principally solutions, ointments and suspensions. However, there are other
dosage forms include:
Intraocular injections Therapeutic contact lenses. Emulsions
Solid hydrophilic inserts. Rate-controlled release systems. New delivery systems ( liposomes).
• The routes of administration for ocular therapeutics can be broadly classified as
1- Topical 2- Peri-ocular 3- Intraocular
4- Systemic 5- Trans-sclera
• To design a drug for successful ocular delivery it demands knowledge of
- Anatomical and physiological factors affecting ocular drug distribution.
- Physico- chemical properties of the drug molecule.
 Eye anatomy
• Three main features:
1- Conjunctiva
• Produce and maintain the tear film.
• Drugs diffusion from conjunctiva is greater than the cornea.
2- Cornea
The cornea is non-vascular and negatively charged, Composed
of three layers:
• Epithelium : a multi-layered epithelium that is rich in lipids.
• Stroma: an aqueous matrix composed of collagen and
keratocytes.
• Endothelium: a single-cellular epithelium that is lipid-rich
and maintains corneal hydration.

➢ Control the paracellular diffusion of drugs into the inner chambers of the eye, so, drugs must exhibit
intermediate solubility, low molecular weight to be effectively absorbed.
 Eye anatomy
3- Lacrimal fluid
• Secreted from glands located on the surface of the eye to remove the therapeutic agent/ formulation
from the surface of the eye.
• The pH of the lacrimal fluid is 7.4 and this fluid possesses a good buffer capacity (due to the presence
of carbonic acid, weak organic acids and protein), being able to neutralise unbuffered formulations
effectively over a wide range of pH values (3.5–10).
• The rate of turnover of lacrimal fluid is approximately 1 µl/min and the blinking frequency in humans
is 15–20 times per minute.
• Notes:
• Aqueous ocular dosage forms: (1) Solutions (major) due to the less complex nature of the
formulation (as compared to suspensions) and greater comfort in use; and (2) suspensions.
• Suspensions required whenever the therapeutic agent exhibits problems regarding chemical stability or,
in the case of steroids (e.g., dexamethasone, prednisolone), the potency of the lipophilic drugs is
greater than that of the water-soluble salts.
 • Advantages of Ocular Dosage forms
• Applied directly to the site of action (higher concentrations)
• Easily performed by the patient.
• Fewer systemic drug effects.
• Disadvantages of Ocular Dosage forms
1- Low ocular bioavailability due to :

A- The poor drug retention at the site of action, due to the low tear volume (7 µl for the
blinking eye, 30 µl for the non-blinking eye). The typical volume of two drops of a solution
formulation is 100 µl and therefore the majority of the applied dose is lost either through
spillage on to the face or via the lacrimal duct.
B- The poor retention time of the applied solutions.
2- Require Special facilities for manufacturing. 3- Local side-effects e.g., pain and irritation.
4- The application of ointment to the eye may result in a temporary blurring of vision.
 Properties of an ideal Ocular Drug Delivery System
1. Control the delivery of drugs of varying physicochemical properties and provide sustained
therapeutic action in the eye with once day administration.

2- It should be non-irritating and non-sensitizing.

3- Sterile and Pyrogen free.

4- Stable in order to allow multiple dosing from a packaged container.

5- Cause no foreign body sensation or interference with vision.

 Factors Affecting the Bioavailability of Ocular Drugs
• 1- Pre-corneal fluid drainage
▪ 80 to 90% of liquid DF drained into the naso-lacrimal duct.

▪ Factors affecting the drainage rate

A. Instilled volume: The rate of solution drainage from the conjunctival sac is directly proportional
to the instilled volume.
B. Viscosity: Increasing viscosity can prolong the residence time of an instilled dose in the
conjunctival sac.
C. pH: The physiological pH of tear fluid is 7.4, instillation of an acidic or alkaline solution causes
excessive tear secretion and loss of drug. N.B.; Ophthalmic preparations must have a pH
between 7 and 7.7 .
D. Tonicity and drug type; Agents such as epinephrine induce tear production, and local anesthetics
such as tetracaine suppress tear production.
 Factors Affecting the Bioavailability of Ocular Drugs

2- Drug binding to tear proteins: result in a reduction in free drug concentrations.

3- Systemic drug absorption: A fraction of the topically applied dose that reaches the nasal mucosa
may be absorbed systemically, leading to potential systemic side effects.
4- Corneal Factors: (hydrophilic layer placed between two lipoid layers).
• Various strategies such as pro-drug derivatives, penetration enhancers, liposomes, and nano-particles
have been employed to deliver drugs across the cornea.
5- Melanin binding: melanin pigment in the iris and ciliary body (Melanin imparts color to the eye).
• Drugs such as ephedrine and timolol can bind to the melanin with a high binding capacity, and only
a small fraction of the bound drug is slowly released.
6- Drug metabolism: Various enzymes in the eye can metabolize the active drug, resulting in
decreased ocular bioavailability.
 Formulation considerations for aqueous ocular dosage forms

1- Choice of drug salt for use in - To achieve the required solubility, maximum pharmacological
ocular solutions effect and low stinging effect.

In suspension: Typically 95% of dispersed particles should

2- Physical properties of the
have an average particle diameter less than 10 µm to
dispersed therapeutic agent
decrease ocular irritation.

The choice of pH should be that which maximises the stability

3- Solution pH/inclusion of
of the drug and increase the absorption of the drug across the
buffers
cornea.

4- Drug absorption across the To be effectively absorbed the drug must exhibit intermediate
cornea solubility or differential solubility, i.e. the ionised and non-
ionised forms coexist.

Aqueous formulation: Purified Water USP. Oil used if the

5- Vehicle
therapeutic agent is unstable within aqueous vehicle.
 Formulation considerations for aqueous ocular dosage forms
1- Choice of drug salt for use in ocular solutions
- To achieve the required solubility, maximum pharmacological effect and low stinging effect.
EX:
Adrenaline bitartrate (pH 3–4) (strong buffer capacity) produce severe stinging.
Adrenaline hydrochloride (pH 2.5–4.5), (medium buffer capacity) and therefore more effectively
neutralised than the bitartrate salt. produce moderate stinging
Adrenaline borate (pH 5.5–7.5) (low buffer capacity and lower acidity ) produce mild stinging.
Increase stinging increase production of lacrimal fluid.
3- Solution pH/inclusion of buffers
Ideally the pH of the ocular solution should be controlled at 7.4 as this is the pH of tear fluid
This is important due to the effect of pH on the stability of alkaloid drugs, e.g. atropine, pilocarpine,
carbochol.
Drug Temp (C) pH Half-life Drug Temp (C) pH Half-life

Pilocarpine
121 6.8 1 hour 121 6.8 34 minutes
Atropine

121 5 60 hours 121 5 24 hours

25 6.8 2 years 25 6.8 66 days
25 5 130 years 25 5 Several years
 Formulation considerations for aqueous ocular dosage forms
4- Drug absorption across the cornea
• The pKa of the therapeutic agent determines the ionisation of the therapeutic agent at defined pH
values.
• To overcome problem of alkaloidal drugs, they are frequently used in the form of the acid salt, where
the pH of the solution will be acidic, and stability is optimised. No buffers are added and therefore
whenever the formulation is instilled into the eye, the lacrimal fluid adjusts the pH to physiological
conditions, thereby facilitating absorption.
• If pH control is required, e.g., for acidic drugs, a borate buffer may be used to produce solutions of
acidic pH (circa 5).
 ❖ Adjutants (additives) used in ophthalmic solutions

• 1- Viscosity-modifying agents
• Mainly hydrophilic polymers added to ocular solutions for three main reasons:
• (1) To control the flow rate of drops from the container ( ease of application)
• (2) Increase the residence time of the solution within the precorneal environment.
• (3) Decrease the lachrymal drainage of the drug.
• The critical formulation viscosity threshold is 55 mPa/s, above which no further increase in contact
time between the dosage form and the eye occurs.
• The upper limit is 30 mPa/s above which may lead to blockage of the lacrimal ducts.
• The enhancement of the viscosity of ocular suspensions will serve to enhance the physical stability of
ocular suspensions.
 • Ideal properties of the viscosity-modifying agent :
• Easily filtered.
• Easily sterilised by filtration or by heat (If chemically and physically stable).
• Compatible with other components: the interaction of hydrophilic polymers with certain
preservatives is a well-known phenomenon and is usually resolved by increasing the concentration
of preservative. e.g. basic therapeutic agents and poly acidic polymers.

• Examples of polymers that are used as viscosity-modifying agents include:

• Hydroxy propyl methyl cellulose (HPMC) (0.45–1.0% w/w).
• Poly(vinyl alcohol) : water-soluble vinyl polymer (0.25 to 3.00% w/w).
• Poly(acrylic acid): water-soluble acrylate polymer that is cross-linked with either allyl sucrose or
allyl ethers of pentaerythritol which predominantly used for treatment of dry-eye syndrome
(keratoconjunctivitis)
 • Adjutants (additives) used in ophthalmic solutions
2- Preservatives
• Ocular formulations are designed as multidose systems, so the addition of a preservative is required.
• Desirable properties of effective an antimicrobial preservative are:
1- Broad spectrum of activity. 2- Compatibility with other ingredients.
3- Nontoxic and nonirritant properties. 4- Chemically stable.
5- Rapid action, soluble in the formulation at the required concentration.

• Cationic preservatives
• The two main cationic preservatives that are commonly used in ocular solutions and suspensions are
benzalkonium chloride and benzethonium chloride.
• N.B. Cationic preservatives are incompatible with anionic therapeutic agents, e.g., pilocarpine
nitrate, physostigmine, and sodium fluorescein (Diagnostic agent for angiography or angioscopy of
fundus and of iris vasculature of eye).
• Furthermore, interaction of these compounds may occur with non-ionic hydrophilic polymers (used to
modify the viscosity of ocular formulations).
 • Benzalkonium chloride
• A mixture of alkyl benzyl dimethyl ammonium chlorides that is used in ocular solutions/suspensions at
a concentration between 0.002 and 0.02% w/v (typically 0.01% w/v).
• Its antimicrobial properties decrease whenever the pH of the formulation falls below 5
• A 0.1% w/v disodium edetate may be added to solve microorganisms resistance (Pseudomonas
aeruginosa) by chelating divalent cations in the outer membrane of the bacterial cell, rendering the
bacteria more permeable to the diffusion of the antimicrobial agent.
• Benzethonium chloride
• It is a pure compound, used in concentration range of 0.01–0.02% w/v (it has lower antimicrobial
activity than benzalkonium chloride).
• Esters of para hydroxy benzoates (parabens)
• Mixtures of methyl and propyl esters of para hydroxy benzoic acid (0.2% w/w).
• Their use is limited because ocular irritancy, and interact with hydrophilic polymers.
 • Organic mercurial compounds
• Contain mercury and, due to environmental and toxicity concerns, are not commonly used in ocular
formulations nowadays.
• Examples are :
1- Phenylmercuric acetate (0.001–0.002% w/v) ,
2- Phenylmercuric nitrate (0.002% w/v ) which is sometimes supplied as a mixture with
phenylmercuric hydroxide, and thimerosal.
3- Thimerosal (0.001–0.15% w/v in ophthalmic solutions) and ( 0.001–0.004 % w/v in suspensions).
• The chronic use (glaucoma) of the phenylmercuric salts has been reported to be deposited in the lens
of the eye (termed mercurialentis).
• Thimerosal is not associated with this problem; however, cause ocular sensitisation. So , these
preservatives are only used in ocular formulations whenever there is no suitable option.
 • Organic alcohols used as preservatives
Chlorobutanol
• Has limited solubility.
• Used at a concentration of 0.5% w/v which is close to the saturation solubility (0.7% w/v at room
temperature). Therefore, if the formulation is stored below room temperature, precipitation of the
preservative may occur in situ.
• It is reserved for acidic ophthalmic preparations as under alkaline conditions, chlorobutanol
hydrolysis, releasing HCl as a by product (the rate of reaction increases with increasing temperature,
e.g. during autoclaving.
• It is volatile and lost from solution if stored in polyolefin containers (due to partitioning). So must be
stored in glass containers.
Phenyl-ethylalcohol
• Has similar properties to chlorobutanol and indeed shares similar problems, e.g. poor solubility,
volatile and partitioning into plastic containers.
• The typical concentration used in ophthalmic preparations is 0.25–0.50% v/v.
 • Adjutants (additives) used in ophthalmic solutions
• 3- Antioxidants E.g., Sodium metabisulphite (0.3%).
• 4- Surface-active agents: Used in aqueous suspension to enhance the physical stability of the
dispersed particles. non-ionic surfactants are preferentially used. whereas the use of anionic
surfactants on ocular solution/suspension dosage forms is avoided due to their potential
toxicity/irritancy.
• 5- Penetration Enhancers: applied to improve the drug/corneal penetration.
▪ These agents act on biological membranes and altering membrane permeability.
▪ EX:
• A) The quaternary ammonium compounds: e.g., benzalkonium chloride.
• B) Mercurial, e.g., thimerosal.
Assignment 1: Enumerate with figures:
• C) Alcohols, e.g., 2-phenylethyl alcohol.
A) 20 marketed ocular preparation contain
• D) Calcium chelators e.g., EDTA
timolol.
• E) Surfactant e.g., palmiloyl carnitine, sodium carpate B) 5 marketed ocular preparation contain
• F) Bile acid and salts e.g., sodium deoxycholate. pilocarpine.
• G) glycoside e.g., saponin and digitonin C) 2 marketed ocular preparation contain
Atropine.
 Manufacture of aqueous ophthalmic formulations
• ophthalmic solutions/suspensions must be sterile.
• The manufacture of these systems may involve at least one of the following steps.
• Production and packaging in the final container under clean conditions followed by sterilisation
by autoclaving (assuming the therapeutic agent is chemically stable under these conditions).
• Production under clean or aseptic conditions followed by aseptic sterilisation by filtration
• If the therapeutic agent is thermolabile then sterilisation by heat should be avoided.
• Clarification of the solution is performed by filtration through an appropriate filter (1 µm), followed
by sterilisation filtration (0.22-µm filter) and packaging (both under aseptic conditions).
• Production under aseptic conditions
• Ophthalmic suspensions may not be sterilised by filtration.
• The sterile therapeutic agent dispersed into the sterile vehicle (with added excipients) and subsequent
packed, both under aseptic conditions.
 Ophthalmic Ointments formulations
• Formulation considerations for Ophthalmic ointments
▪ Drugs administered as ointments have better bioavailability than drops primarily owing to;
• - Prolonged corneal contact time.
• - Reduced drainage through the nasolacrimal duct. .
• One major disadvantage associated with the use of ophthalmic ointments is their general
greasiness and the associated (temporary) blurring of vision. For these reasons patients may prefer
aqueous ocular formulations or, alternatively, may prefer to reserve the use of ophthalmic ointments
to night-time application.
• The frequency of administration of ointments is generally lower than their aqueous-solution
counterparts due to their greater retention within the precorneal region (approximately 2–4 times
greater than for aqueous solutions).
• As is the case for all ointment formulations, ophthalmic ointments are prepared by dispersion of the
therapeutic agent in the pre-prepared ointment base.
 Ophthalmic Ointments Bases
• Hydrocarbon bases
• Widely used in ophthalmic ointments and are generally composed of a mixture of paraffins (to achieve
the correct viscosity).
• yellow soft paraffin is preferred to white soft paraffin: however white soft paraffin associated with a
lower potential for ocular irritancy. N.B. White soft paraffin is a bleached form of yellow soft paraffin
• Non-emulsified absorption bases
• Composed of one or more paraffins (e.g. liquid and yellow soft paraffin) and a sterol containing
emulsifying agent (e.g. lanolin derivatives).
• Less greasy than hydrocarbons alone, in addition, aqueous solutions of drug may be incorporated into
non-emulsified absorption bases.
• Water-soluble bases/aqueous gels
• Associated with a lower incidence of blurred vision (due to their water-miscibility).
• Primarily formulated using polyethylene glycols.
• Aqueous gels composed of poly(acrylic acid) can be employed for the treatment of glaucoma.
 • Excipients in ocular ointments
• The nature of the excipients is dependent on the nature of the ointment base.
• Hydrocarbon- bases and bases contain lower concentrations of water require no further excipients.
Exceptionally the inclusion of non-aqueous antioxidants, e.g. butylated hydroxytoluene,
butylated hydroxy-anisole, if the therapeutic agent is prone to degradation by oxidation.
• Aqueous systems, e.g. poly(acrylic acid) gels (which may contain 95% w/w water),
the same types of excipients that are commonly employed in aqueous solutions.
• Manufacture of Ophthalmic Ointments Formulations
• Similar to ointment formulations; however, ophthalmic ointments must be sterile.
• Due to their high viscosity, terminal sterilisation of ointments is a difficult operation and may only
be performed (in limited examples) at elevated processing temperatures. Therefore, ointments are
typically manufactured and packaged under aseptic conditions.
• The components of the base are prepared in an enclosed mixing vat to which heat may be applied
both to aid dissolution and mixing of the ingredients and, importantly, to sterilise the ointment base.
• The sterile therapeutic agent may then be added to the sterile base and mixed until homogeneous.
Filling of the ointment into the final container is performed under aseptic conditions.