OPHTHALMIC PRODUCTS

DEFINITION

Ophthalmic preparations are sterile products essentially free from foreign particles, suitably compounded & packaged for instillation into the eye.

CHARACTERISTICS
‡ CLARITY ‡ BUFFER & pH ‡ TONICITY ‡ STERILITY ‡ PRESERVATIVES ‡ ANTIOXIDANTS ‡ VISCOSITY ‡ FOREIGN PARTICLES ‡ SURFACE ACTIVITY

CLARITY
1. Ophthalmic solutions must be free from foreign particles, which is generally accomplished by filtration. The filtration process also helps to achieve clarity of the solution. Wetting/clarifying agents used for ophthalmic preparations. ‡ ‡ ‡ Agent Usual Concentration (%)

2. 3.

Polysorbate 20 - 1% Polysorbate 80 - 1%

FOREIGN PARICLES
‡ All the ophthalmic products should be clear and free foreign particles, fibers and filaments. ‡ Ophthalmic solutions should be clarified very carefully by passing through bacteria proof filters, such as, membrane filters and sintered glass filters. ‡ The particle size of the eye suspension should be in a ultra fine state of subdivision to minimize irritation. ‡ A separate filter should be used for different ophthalmic products in order to avoid the contamination

VISCOSITY
‡ An increase in the viscosity of ophthalmic products will result in a longer residence time in the eye, providing a longer time for drug absorption and effect. ‡ Various thickening agents are added in the ophthalmic preparations. These agents improve the viscosity of the preparation. ‡ The thickening agents are not included in the formulation of drops and eye lotions which are required to be used during or after surgery due to some possible adverse effects on the interior of the eye.

Thickening agent properties
‡ It should be easy to filter ‡ It should be easy to sterilize ‡ It should be compatible with other ingredients ‡ It should posses requisite refractive index and clarity level

Thickening agents
AGENT ‡ Hydroxyethylcellulose ‡ Hydroxypropyl methylcellulose ‡ Methylcellulose ‡ Polyvinyl alcohol ‡ polyvinylpyrrolidone ‡ Carboxy methylcellulose ‡ Polyethylene glycol USUAL CONCENTRATION 0.8 1.0 2.0 1.4 1.7

PRESERVATIVES
‡ Most ophthalmic solutions/suspensions are prepared in multiple use containers, they must be preserved. The selected preservative must be compatible with the active drug as well as all the other excipients in the product.

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Preservative name ‡ ‡ Chlorobutanol

Usual conc.

Conc. Range 0.5

max. conc

Quaternary ammonium compounds 0.01 0.004-0.02 0.013 0.01 0.001-0.01 0.004 0.004 0.01 0.1

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Benzalkonium chloride Benzethonium chloride Organic mercurials Phenylmercuric acetate Phenylmercuric nitrate Thimerosal Parahydroxybenzoates

ANTIOXIDANTS
ANTIOXIDANT USUAL CONCENTRATION 0.1% 0.1% 0.1% 0.1%

‡ Ethylenediaminetetraaceticacid ‡ Sodium bisulfite ‡ Sodium metabisulfite ‡ Thiourea

SURFACE ACTIVITY
‡ Vehicles used in ophthalmic preparation must have good wetting ability to penetrate cornea and other tissues. ‡ Certain surfactants or wetting agents are added which are found suitable for ophthalmic products. ‡ It should not cause any damage to tissues of eye. E.g.: Benzalkonium chloride Polysorbate 20 Polysorbate 80 Dioctyl sodium sulpho-succinate

STERILITY
‡ Ophthalmic solutions must be sterile. Sterility is best achieved through sterile filtration using a sterile membrane filter of 0.45 or 0.2 micron pore size and filtering into a sterile container. Other methods of sterilizing ingredients include dry heat, steam under pressure (autoclaving) and gas sterilization (ethylene oxide). To maintain in multidose container containing ophthalmic products, a suitable preservative is added. The preservative should be non-toxic, nonirritant and should be compatible with medicaments.

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TONICITY
‡ Lacrimal fluid has an isotonicity value equivalent to that of a 0.9% sodium chloride solution. However, the eye can tolerate a value as low as 0.6% and as high as 1.8% sodium chloride equivalency. E.g. Sodium chloride, boric acid and dextrose are commonly used.

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pH & BUFFER
‡ pH plays an important role in therapeutic activity, solubility, stability and comfort to the patient. ‡ Tears have a pH of about 7.4 ‡ Alkaloidal salt solutions are stable at pH 2 to 3 but this pH is irritant to the eye. ‡ Ophthalmic solutions are buffered at the pH of maximum stability for the drug (s) ‡ The buffers are included to minimize any change in pH during the storage life of the drug ‡ This can result from absorbed CO2 from the air or from hydroxyl ions from a glass container.

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Changes in pH can affect the solubility and the stability of drugs It is important to minimize fluctuations in pH The buffer system should be designed sufficient to maintain the pH throughout shelf-life of the product This is accomplished by using low concentration of the buffers salts Generally a buffer capacity less than 0.05 is desired. pH in the range of 4-8 is considered optimum.

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OPHTHALMIC PRODUCTS
‡ EYE DROPS ‡ EYE LOTIONS ‡ EYE OINTMENTS ‡ EYE SUSPENSIONS ‡ CONTACT LENS SOLUTIONS ‡ OPHTHALMIC GELS ‡ OPHTHALMIC SOLUTIONS ‡ POWDER FOR SOLUTIONS ‡ GEL FORMING SOLUTIONS

EYE DROPS
‡ Eye drops are sterile aqueous or oily solutions or suspensions of drugs that are instilled into the eye with a dropper. ‡ Drugs having antiseptic, anti-inflammatory mydriatic or meiotic properties

Essential characteristics of Eye drops
‡ Sterile ‡ Iso-osmotic with lachrymal secretions ‡ Free from foreign particles, fibres and filaments ‡ Almost neutral pH ‡ Preserved with a suitable bactericide ‡ They should remain stable during its storage

Formulation of Eye-drops
‡ Preparation of bactericide and fungicidal vehicle The aqueous or oily vehicles is used in the preparation of eye drops. The aqueous vehicles may support bacterial growth, then bactericide may be used to preserve the eye drops    phenylmercuric nitrate/acetate ± 0.002% benzalkonium chloride ± 0.01% chlorohexidine acetate ± 0.01% the medicaments are dissolved in the aqueous vehicle containing suitable antimicrobial agent ‡ Clarification It clarified by passing the solution through membrane filter having pore size of 0.8 m. The clarified solution is immediately transferred into the final containers and sealed to exclude micro-organism

‡ Preparation of solution of medicaments and adjuvants

‡ Sterilization it is sterilized by autoclaving or heating with bactericide at 98o to 100o C for 30 mins. or filtration through bacteria proof filter ‡ Containers ‡ Labelling it should be labelled µFOR EXTERNAL USE ONLY¶ along with storage conditions to maintain full activity

Single dose containers

Plastic containers

Glass containers

Sterilization
Autoclave:

Adjuvants used in the preparation of Eye-drops
‡ Thickening agents ‡ Buffers ‡ Anti-oxidants ‡ Wetting agents ‡ Isotonicity adjustment substances

Precautions
‡ If the dropper is separate, always hold it with its tip down ‡ Never touch the dropper surface ‡ Never rinse the dropper ‡ Never use eye-drops that have changed colour ‡ When the dropper is at the top of the bottle, avoid contaminating the cap when removed ‡ After installation of drops, do not close eyes tightly or blink more often than usual as this may remove the medicine from the place where it is needed

Example
Atropine eye-drops ‡ Atropine sulphate ‡ Phenyl mercuric nitrate solution 0.002% ‡ Purified water, add upto make an eye-drops Direction To be used as directed 1g 50.0ml

EYE LOTIONS
‡ The drug is dissolved in a non aqueous vehicle such as castor oil & emulsified with water using a Non-ionic surfactant. ‡ Sodium chloride, sodium bicarbonate, boric acid, borax or zinc sulphate are mainly used drugs Eg. Sodium Chloride eye lotion B.P.C ‡ ‡ Sodium chloride ± 9g Purified water to produce ± 1000ml

‡ Eye lotion are normally used for eye bath and for first aid

Types 1.Sterile Aqueos Solution Containing No Bacteriocidal (For 24 Hrs) 2. Sterile Aqueos Solution Containing Bacteriocidal (For One Week)

EYE OINTMENTS
‡ Ophthalmic Ointments are anhydrous contain mineral oil & white petrolatum as the base ingredients. Eg: Atropine eye ointment. Atropine sulphate ± 1 g Sterile base ± 100 mg Prepare an eye ointment Sterile base contains Liquid paraffin - 10g Wool fat ± 10g Yellow soft paraffin ± 80g Advantage: 1. long contact time. 2. Greater bioavailability.

EYE SUSPENSIONS
‡ Suspensions are dispersions of finely divided, insoluble drug substances in an aqueous vehicle containing suitable suspending agent and dispersing agents. They are prepared in the case of the drug is insoluble in the desired vehicle or unstable in liquid form It is also used to produce the sustained action

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Disadvantage: ‡ ‡ Particle size may cause irritation to the eye. Always require prick shaking before use.

Essential characteristics
‡ They should be sterile ‡ They should have desired viscosity ‡ They should be isotonic ‡ The particle size of the eye-suspension should be fine enough so that it should be non irritating to the eye ‡ They should be shaken thoroughly before use in order to distribute the drug particles uniformly ‡ They should be packed in a suitable container, so that it can be easily instilled into the eye

CONTACT LENS SOLUTIONS
‡ HARD LENSES 
A wetting solution and soaking/ storing / decontaminating solution is required  Ist ± suitable for placing in the eye  IInd ± Have contact with the eye WETTING SOLUTIONS:  Achieve a rapid wetting by lachrylal fluid and promote comfort  Facilitate insertion of lens  Provides cushioning and lubrication  Non irritants

‡ It contain  Wetting agent / polysorbate 80, polyvinyl alcohol  Antimicrobial agent / BZK 0.004%, EDTA 0.1%  Tonicity / 0.92 ± 1.1% NACl  Buffering agent pH 8.02 ± 8.8  Boric acid and Borox buffer  Thickening agent ± Hypromellose Storing solution: Purpose  Achieves cleaning and microbial inactivation  Hydrating  It contains surface active agents, pH 7.4, Antimcirobials

SOFT LENS Purpose  To remove deposit such as lipoprotein adhering to lens after wear  It contains viscolizing surface active agents / hyper mellose  Antibacterial BZK 0.004% STORING SOLUTION Purpose  Hydrating, cleaning, inactivation of microbial contamination  It contains antibacterial / 3% H20 active against keratitis contamination  Poly guad ± Poly quaternium compound recently introduced in soft lens neither adsorbed or absorbed by lens and it has low toxicity to corneal and occular tissue

CONTAINERS
‡ Usually packed in plastic containers ‡ Containers are kept in hygienic condition by keeping them scrupulously clean and using disinfecting / storage solution wear

OPHTHALMIC SOLUTIONS
‡ ‡ Most common dosage form for delivering drugs to the eye Ingredient are completely soluble thus uniformity of the product can achieve Eg. Isotonic Sodium Chloride Solution Disadvantage: ‡ ‡ More contact time by high viscosity of solution viscous soln can produce a residue on eyelashes.

GEL FORMING SOLUTIONS
‡ ‡ It contain polymer soln at a low viscosity liquid & gel forms on contact with the eye fluid when increases contact time, is increased drug absorption & prolonged duration of therapeutic effects Gel phase transition occurs by T0, pH ,ionic strength or presence of tear proteins.

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Advantage:

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lowering the contineous dose frequency

POWDERS FOR SOLUTIONS
‡ Drugs that have very limited stability in aqueous solution can be prepared as sterile powers for reconstitution at prior to dispensing.

OPHTHALMIC GELS
‡ Gel forming polymers (carbomer) used to develop aqueous, semisolid dosage forms ‡ The viscous gels have significant increased topical residence time & can increase drug bioavailability & decrease dosage frequency compared to solutions. Eg: carbomer gel of pilocarpine. Disadvantage: ‡ Blurring of vision

PREPARATION PILOCORPINE GEL
‡ Pilocorpine Hcl ‡ Benzalkonium chloride -4% -0.008%

‡ Disod. Edetate, carbomer940, sod.hydroxide, - q.s ‡ Purified water process: ‡ Carbomer dissolved in one portion of water and autoclaved. -100 ml

‡ Pilocorpine Hcl, Benzalkonium chloride, Disod. Edetate, sod.hydroxide are dissolved in another part of water filter through membrane filter. ‡ Carbomer solution is added into the pilocarpine solution under aseptic condition. ‡ Final volume is adjusted with sterile water.

QUALITY CONTROL FOR OPHTHALMIC PRODUCTS
‡ 1. 2. 3. Three main areas of quality control. They are«. Incoming stock Manufacturing (processing) Finished products.

Incoming stocks
‡ For sterile products, incoming stock control encompasses routine tests on all ingredients as well as special evaluation such as -Pyrogen test on WFI -Glass tests on container -Identity test on rubber closures ‡ Also necessary to perform microbial load tests to determine the number and types of microorganism present in the formulation.

MANUFACTURING (PROCESSING)
‡ Sterile products involves all of the innumerable testes, readings & observations made throughout the manufacturing process of a products such as, (a) conductivity measurements during the distillation of WFI. (b) conformation of volume of fill in product containers. (c) Recording of cycle time & temperature for thermal sterilization of the products (d) Conforming the count and identity of labels for the product.

FINISHED PRODUCTS
(i) (ii) All of the final assays & tests to which the product is subjected. Chemical & biological tests such as a) LEAKER TEST b) CLARITY TEST c) PYROGEN TEST d) STERILITY TEST

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