Ophthalmic Preparations

By Dr. Mohamed Ali Attia Shafie

Prof. of Pharmaceutical Technology GUC
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Anatomy of the Eye .

Ophthalmic Preparations
Pharmaceutical preparations are applied topically to the eye to treat surface or intraocular conditions including infections of the eye or eyelids due to bacterial, fungal and viral .

Forms of Ophthalmic Preparations :

Solutions , Suspensions , Gels , Ointments , and Ocular Inserts .
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The preparation of solutions and suspensions for ophthalmic use requires special considerations :

1. Sterility 2. Iso-tonicity 3. Buffering 4. Preservation 5. Viscosity 6. Packaging 1. To maintain sterility during patient use , antimicrobial agents are included in ophthalmic formulation . Ophthalmic solution / Suspensions must be sterilized in their final containers by autoclaving at 121 C for 15 minutes . This method sometimes precluded by the thermal instability of the formulations components . A alternative bacterial filters may be used .
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Examples of Antimicrobial Agents

Antimicrobial Agent Benzalkonium Chloride Benzethonium Chloride Chlorobutol Concentration Range 0.004 0.01% 0.01% 0.5%

Phenylmercuric Acetate
Phenylmercuric Nitrate

0.004%
0.004%

Thiomersal

0.005 0.01%
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Properties of Antimicrobial Agent

1. Stability e.g. Chlorobutanol degraded during autoclaving .
2. Chemical/physical compatibility with other formulation and packaging components . 3. Effective at concentration used . 4. Safe at the concentration used .
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2. Isotonicity
If a solution is placed behind membrane that is permeable only to solvent molecules and not to solutes molecules ( semi-permeable membrane ) a phenomenon called osmosis occurs as the molecules of the solvent traverse the membrane .

Osmotic Pressure
The solvent passes into the more concentrated solution until equilibrium is established on both sides of the membrane and an equal concentration of solute exists on the two sides . The pressure responsible for this movement is termed osmotic pressure .

Body fluids including blood and lacrimal fluid, have an osmotic pressure corresponding to that of a 0.9% solution of sodium chloride . The term isotonic used only with reference to a specific body fluid whereas iso-osmotic is a physical-chemical term which compares the osmotic pressure of two liquids which may or may not be physiologic fluids . Solutions either lower osmotic pressure than body fluids are referred to as hypotonic , whereas solutions having a greater osmotic pressure are termed hypertonic .
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Isotonicity ( Contd )

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3. Buffering
The pH of an ophthalmic preparation may be adjusted and buffered for one or more purposes :
1. 2. 3. 4. 5. For greater comfort to the eye . To render the formulation more stable . To enhance the aqueous solubility of the drug . To enhance the drugs bioavailability . To maximize preservative efficacy .

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3. Buffering ( Contd.. )
The pH of normal tears is considered to be about 7.4 but varies among patient ( e.g. more acidic in contact lens wearers ) . 4. Viscosity and Thickening Agents . The role of thickening agents is to increase the viscosity which lead to increase the contact time with the tissues to enhance therapeutic effectiveness . Examples : HPMC, PVA, MC .

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Ocular Bioavailability
Physiological Factors which affect drugs ocular bioavailability . 1. Protein binding . 2. Drug metabolism . 3. Lacrimal drainage .
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1. Protein Binding .
Protein-bound drugs are incapable of penetrating the corneal epithelium due to the size of the protein-drug complex . Because the short time in which an ophthalmic solution may remain in the eye ( dye to lacrimal drainage ) the protein binding of the drug substance could prevent its therapeutic value by rendering it unavailable for absorption . Although ocular protein binding is reversible, tear turnover results in the loss of both bound and unbound drug .
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2. Drug Metabolism
Tears contain enzymes ( e.g. lysozyme ) capable of metabolic degradation of drug substances .

Other Factors Affecting Ocular Bioavailability

a. Physico-Chemical characteristics of drug . b. Product formulation . Because the cornea is a membrane barrier containing both lipophilic and hydrophilic layers, it is permeated mostly by drug having both lipophilic and hydrophilic characteristics .
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Composition of Cornea .
Epithelium layer : lipophilic Stroma layer : hydrophilic Endothelium layer : lipophilic

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Additional Considerations .
Ophthalmic solutions must be clear and free of all particulate matter for patient comfort and safety . The formulation of an ophthalmic suspension may be undertaken when it is desired to prepared product with extended corneal time, or it may be necessary when the drug is insoluble or unstable in an aqueous vehicle . Drug particles in an ophthalmic suspension must be finely subdivided ( micronized ) to minimize eye irritation and/or scratching of the cornea . The suspended particles must be easily and uniformly redistributed by gentle shaking of the container prior to use .
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Semisolid Ophthalmic Preparations .

Oleaginous ointment bases are the main semisolid dosage forms which are currently used in ophthalmology . These ointment bases are suitable for those drugs that are liable to be hydrolyzed . The main disadvantage of the use of ophthalmic ointments is their greasy nature and blurring of Vision . They are used at night . The ophthalmic ointments also, contain preservatives in the same concentration as in aqueous systems . The ophthalmic ointments are characterized by having a prolonged retention time and increase in the ocular contact time of the drug .
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Solid Ophthalmic Preparations .

This type of ophthalmic products include : 1. Non-erodible ocular inserts .

2. Erodible ocular inserts .

3. Contact lenses .

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1. Non-erodible Ocular Inserts

The ocusert is a membrane which is soft and flexible and designed to be placed in the cul-de-sac between the sclera and the eyelid and continuously release the drug at a steady rate for long time . Ocusert has three major components : 1. The drug . 2. The drug delivery module . 3. A plat form .

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1. Non-erodible Ocular Inserts ( Contd.. )

The drug delivery module consist of a. A drug reservoir ( Drug + Carrier material ) b. A rate controller membrane ( ethylene vinyl acetate ) c. Annular ring of the membrane .

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2. Erodible Ocular Inserts

These solid inserts absorb the aqueous tear fluid and gradually erode or disintegrate . The drug is slowly leached from the matrix and they quickly loss their solid integrity . They possess an advantage over the non erodible membrane or soft contact lens inserts, they do not have to be removed at the end of the therapy .

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3. Contact Lenses
Contact lenses are classified according to their chemical composition and physical properties into : 1. Hard contact lenses .

2. Soft contact lenses .

3. Rigid gas permeable ( RGP ) .

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1. Hard Contact Lenses .

The lenses are termed hard because they are made of a rigid plastic resin, polymethylmethacrylate ( PMMA ) . The lenses are 7 10 mm in diameter and are designed to cover only part of the cornea . Hard lenses require an adoption period sometimes as long as a week for wearing comfort . PMMA lenses are practically impermeable to oxygen and moisture, a disadvantage to corneal epithelial respiration and to patient comfort .

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2. Soft Contact Lenses .

Are more popular than hard lenses because of their greater comfort . They range from about 13 to 15 mm in diameter and cover the entire cornea . Because of their size and coverage, soft lenses are less likely than hard lenses to dislodge spontaneously . They also are less likely to permit irritating foreign particles ( such as dust ) to lodge beneath them . They are less durable than hard contact lenses and carry some risk of absorbing medication which may be concomitantly applied to the eye .
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2. Soft Contact Lenses ( Contd.. )

Soft contact lenses are made of a hydrophilic transparent plastic, hydroxyethylmethacrylate ( HEMA ) With small amounts of cross-linking agents that provide a hydrogel network . Soft lenses contain between 30 and 80% water which enables enhanced permeability to oxygen . Types of soft contact lenses . 1. Daily wear or disposable : do not require cleaning and disinfection because they are discarded and replaced with a new pair . 2. Extended Wear .
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3. Rigid Gas Permeable ( RGP )

They are constructed of material that is oxygenpermeable but hydrophobic . Compared to hard lenses they permit greater movement of oxygen through the lens , while retaining the characteristics durability and ease of handling . RGP lenses provide greater wearing comfort than hard lenses .

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Care of Contact Lenses

All soft contact lenses require a routine care program that include :
1. Cleaning to loosen & remove lipid and protein deposits . 2. Rinsing to remove the cleaning & material loosened by cleaning . 3. Disinfection to kill microorganisms .
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Care of Contact Lenses ( Contd.. )

Hard contact lenses require a routine care program that include : 1. Cleaning to remove debris & deposits from the lens .

2. Soaking the lens in a storage disinfecting solution while not in use .

3. Wetting the lenses to decrease their hydrophobic characteristics .
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Types of Solutions are used in the Care of Contact Lenses .

1. Cleaning solution .
2. Soaking solution .

3. Wetting solution .
4. Combination purpose solutions .

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Solutions for Soft Contact Lenses .

Cleaners : Because of their porous composition, soft lenses tend to accumulate proteinaceous material which form a film on the lens, decreasing clarity and serving as a potential medium for microbial growth . Two main categories of cleaners are : Surfactants which emulsify accumulated oils, lipids & inorganic compounds, and enzymatic cleaners which break down and remove protein deposits .
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Composition of Cleaning Solution

The cleaning solution is composed of : Nonionic detergent , Wetting agent Chelating agent , Buffer, Preservatives Enzymatic cleaning is accomplished by soaking the lenses in a solution prepared from enzyme tablets . The enzyme tablets contain either pancreatin , or subtilisin, which causes the hydrolysis of protein to peptides and amino acids .

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Rinsing/Storage Solutions
Saline solutions for soft lenses should have a neutral pH and be isotonic with human tears ( 0.9% ) . Besides rinsing the lenses , these solutions are used for storage because saline maintains there curvature diameter and optical characteristics . The solutions also facilitate lens hydration, preventing the lens from drying out and becoming brittle .

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Disinfection and Neutralization .

Disinfection can be accomplished by either of two methods : 1. Thermal ( heat ) 2. Chemical ( No heat ) .
Thermal disinfectant The lenses are placed in heating unit with saline solution . The solution is heated to kill microorganisms ( 80 C for 10 minutes ) .

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Chemical disinfection
Free radicals chemically released from the peroxide react with the cell wall of the microorganisms . Further, the bubbling action of the peroxide promote the removal of any remaining debris on the lens . To prevent eye irritation from residual peroxide after disinfection, it is necessary that the lenses be exposed to one of three types of neutralizing agents : 1. Catalytic type : an enzyme catalase . 2. Reactive type : as sodium pyruvate or sod. thiosulfate . 3. Dilution elution type .
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Care Regimen For Soft Lenses .

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Packaging of Ophthalmic Solutions .

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